Distal vacuolar myopathy in nephropathic cystinosis

Abstract

Nephropathic cystinosis is a lysosomal storage disorder leading to renal failure by age 10 years. Prolonged patient survival following renal transplantation has allowed the development of previously unknown long-term complications. Muscle involvement has been reported in a single posttransplant cystinosis patient, but the range of clinical, electrophysiologic, and histologic features has not been fully described. Thirteen of 54 post-renal-transplant patients that we examined developed weakness and wasting in the small hand muscles, with or without facial weakness and dysphagia. Tendon reflexes were preserved and sensory examinations were normal. Electrophysiologic studies in 11 affected patients showed normal nerve conduction velocities and preserved sensory action potentials. The voluntary motor units in the affected distal muscles had reduced amplitude and brief duration, confirmed with quantitative electromyography in 4 patients. Biopsy of the severely affected abductor digiti minimi or extensor carpi radialis brevis muscles in 2 patients revealed marked fiber size variability, prominent acid phosphatase-positive vacuoles, and absence of fiber type grouping or inflammatory cells. Crystals of cystine were detected in perimysial cells but not within the muscle cell vacuoles. The muscle cystine content of clinically affected muscles was markedly elevated. We conclude that a distal vacuolar myopathy is a common late complication of untreated nephropathic cystinosis. Although the cause is unclear, the general lysosomal defect in this disease may also affect the lysosomes within muscle fibers.

Successful treatment of the murine model of cystinosis using bone marrow cell transplantation

“…4 Cystine crystals were observed in fibroblastic cells adjacent to muscle fibers and within perimysial collagen fibrils, and muscle necrosis was also observed. 39 The Ctns Ϫ/Ϫ mice also present with muscular impairment associated with cystine crystals located in interstitial cells and myocyte necrosis. 14 Cardiomyopathy can be a late complication in cystinosis, 4 and one autopsy revealed the presence of cystine crystals in interstitial cardiac histiocytes and one myocardial cell.…”

The Genomic Region Encompassing the Nephropathic Cystinosis Gene (CTNS): Complete Sequencing of a 200-kb Segment and Discovery of a Novel Gene within the Common Cystinosis-Causing Deletion

“…Once the function of the latter protein has been elucidated and its putative substrate(s) identified, it will be important to study the clinical features of cystinosis patients harboring different CTNS deletions (e.g., those with or without the common 57-kb deletion). It is possible that the presence/absence of CARKL may account for the clinical heterogeneity seen in cystinosis patients with respect to distal vacuolar myopathy (Charnas et al 1994), nephrocalcinosis (Theodoropoulos et al 1995), and other complications of the disease (Gahl and KaiserKupfer 1987;Gahl et al 1995). In this regard, we hypothesize that CARKL may be a modifier for the cystinosis phenotype.…”

“…The classic disorder is characterized clinically by renal tubular Fanconi syndrome in the first year of life, growth retardation in childhood, renal glomerular failure at ∼10 years of age, hypothyroidism, and a variety of other complications, including photophobia and corneal crystal formation (Gahl 1986;Gahl et al 1995). After renal transplantation, cystine accumulation continues in nonrenal organs, frequently causing a distal vacuolar myopathy (Charnas et al 1994), swallowing difficulty (Sonies et al 1990), or retinal dysfunction (Kaiser-Kupfer et al 1986), and occasionally causing diabetes mellitus (Fivush et al 1987), pancreatic exocrine insufficiency (Fivush et al 1988), or neurological deterioration (Ehrich et al 1979;Fink et al 1989). These complications arise because defective lysosomal transport of the disulfide cystine (Gahl et al 1982a) causes this amino acid to accumulate within the lyso-somes of many different cell types, which then triggers cystine crystal formation (Gahl et al 1982b).…”

Coronary Artery and Other Vascular Calcifications in Patients with Cystinosis after Kidney Transplantation

“…Infants with cystinosis are normal at birth but develop renal tubular Fanconi syndrome at 6 to 12 mo of age and renal failure at approximately 10 yr of age (8). In addition, hypothyroidism (1,2), myopathy (9,10), swallowing dysfunction (11), diabetes (12), male hypogonadism (13), pulmonary dysfunction (14), and central nervous system involvement (15)(16)(17) complicate this disorder in adolescence and early adulthood (18).…”