Abderhalden-Kaufmann-Lignac syndrome: Description, Causes and Risk Factors:
A lysosomal storage disorder with various forms, all with autosomal recessive inheritance. The nephropathic form of early childhood is characterized by widespread deposits of cystine crystals throughout the body, including the bone marrow, cornea, and other tissues, with mild elevation of plasma cystine and cystinuria; associated with a marked generalized aminoaciduria, glycosuria, polyuria, chronic acidosis, hypophosphatemia with vitamin D-resistant rickets, and often with hypokalemia; other extrarenal manifestations include photophobia and hypothyroidism; due to a defect in the transport of cystine across lysosomal membranes caused by mutation in the CTNS gene on 17p. There is a milder form with onset in adolescence and one with onset in adulthood without kidney damage; the latter two forms are thought to be allelic to the nephropathic form of early childhood.
Abderhalden-Kaufmann-Lignac syndrome is an autosomally determined recessive genetic disorder that results from a defect in the lysosomal ef?ux of cystine. This is caused by mutations in the gene, CTNS, that encodes the transporter cystinosin, which mediates the ef?ux of cystine from the lysosome to the cytosol. A defect in the CTNS gene leads to a high level of cystine accumulation in the lysosome.
It is transmitted by a recessive autosomal mechanism. This means that a person must inherit two changed copies of the same gene in order to have Abderhalden-Kaufmann-Lignac syndrome. If a person inherits one changed gene and one normal gene, then that person will be a healthy carrier. If both parents are carriers of the same changed gene, they may pass on either their normal gene or their changed gene to their child.
RESEARCH: A mouse model has been created by homozygous knockouts of the CTNS gene, and these ctns-/ctns- mice showed cystine accumulation in all organs. However, while the mice displayed ocular and other symptoms of the disease, surprisingly, they did not show proximal tubular dysfunction in the kidney or renal failure. Using the mouse model, bone marrow transplantations were recently performed and shown to be very successful in the treatment of the disease in mice, raising hopes for a similar treatment being eventually possible in humans.
Several investigations over the past several years have been directed towards understanding how increased lysosomal cystine leads to the clinical symptoms and subsequent manifestations. However, despite many years of study, the pathophysiology of the disease is still not properly understood.
One suggested mechanism by which intralysosomal cystine accumulation is linked to the clinical manifestations is that the increased cystine levels in the lysosome lead to enhanced apoptosis. This has been based on the 2-4-fold increased rate of apoptosis seen in cystinotic cells, which is reversed when cysteamine treatment decreases the lysosomal cystine levels. It has been suggested that during the early stages of apoptosis when the lysosomal membrane is permeabilized, large amounts of cystine exit the lysosome to enter the cytosol and positively affect the proapoptotic proteins (such as protein kinase C?) leading to enhanced apoptosis.
A second mechanism that may explain the biochemical basis for the pathophysiology is based on the observation that lysosomal cystine accumulation leads to cellular ATP depletion. ATP depletion in cystinosis was ?rst observed in a cystinosis model (based on loading lysosomes with cystine by cystine dimethyl ester, CDME. In this study, it was also further suggested that the decreased ATP in cystinotic cells would lead to a decrease in Na+K+-ATPase activity. As this pump generates a Na+ gradient that allows reabsorption of amino acids, phosphate, glucose and other solutes in the proximal tubules of the kidney, defective pumping owing to decreased ATP levels would decrease uptake and thus lead to the severe phenotypes. As the CDME model of cystinosis is not a fully acceptable model owing to the oxidative stress induced by CDME itself, ?broblast cells from cystinotic patients have also been used to investigate the disease. It was observed that signi?cant ATP depletion also occurs in cystinotic ?broblast cells. However, whether ATP depletion is a triggering factor leading to the clinical manifestations has not been conclusively established.
Affected children are developmentally delayed with dwarfism, rickets and osteoporosis. Renal tubular disease is usually present causing aminoaciduria, glycosuria and hypokalemia.Cysteine deposition is most evident in the conjunctiva and cornea.
Diagnosis of Abderhalden-Kaufmann-Lignac syndrome is confirmed by measuring cystine levels in polymorphonuclear leukocytes or cultured fibroblasts. Cystine concentrations in individuals who are homozygous for cystinosis are 5-10 nmol half-cystine/mg cell protein; in heterozygous individuals, the levels are less than 1 nmol half-cystine/mg cell protein. 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.
Serum electrolyte measurements are used to detect the presence of acidosis (hyperchloremic, normal anion gap and severity of hypokalemia, hyponatremia, hypophosphatemia, and low bicarbonate concentration in patients with cystinosis.
- Blood gases may be used to detect metabolic acidosis and the degree of respiratory compensation.Urine testing reveals low osmolality, glucosuria, and tubular proteinuria (including generalized amino aciduria).
- Measurements of urine electrolytes serve to detect the loss of bicarbonate and phosphaturia.
Renal ultrasonography should be obtained in patients with elevated urine calcium excretion to rule out nephrocalcinosis.
- Radiography for kidneys, ureter, and bladder (KUB) may be needed to evaluate possible urinary tract calcifications in patients with hypercalciuria or as a diagnostic evaluation of severe abdominal pain.
- CT scanning and MRI are used to evaluate adult patients with infantile nephropathic cystinosis who have CNS symptoms.
Elevated level of cystine in white blood cells
- Presence of cystine crystals in the cornea on slit-lamp examination.
- Determination of the white blood cell (WBC) cystine level is the key measurement for the diagnosis of Abderhalden-Kaufmann-Lignac syndrome and for monitoring the effectiveness of the treatment.
Abderhalden-Kaufmann-Lignac syndrome is normally treated with a drug called cysteamine (brand name Cystagon). The administration of cysteamine can reduce the intracellular cystine content. Cysteamine concentrates inside the lysosomes and reacts with cystine to form both cysteine and a cysteine-cysteamine complex, which are able to leave the lysosomes. When administered regularly, cysteamine decreases the amount of cystine stored in lysosomes and correlates with conservation of renal function and improved growth. Cysteamine eyedrops remove the cystine crystals in the cornea that can cause photophobia if left unchecked. Patients with Abderhalden-Kaufmann-Lignac syndrome are also often given sodium citrate to treat the blood acidosis, as well as potassium and phosphorus supplements. If the kidneys become significantly impaired or fail, then treatment must be begun to ensure continued survival, up to and including renal transplantation.
Side Effects: Positive.
NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.
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