Cystinosis distal myopathy, novel clinical, pathological and genetic features

Abstract

Nephropathic cystinosis is an autosomal recessive lysosomal disease in which cystine cannot exit the lysosome to complete its degradation in the cytoplasm, thus accumulating in tissues. Some patients develop a distal myopathy involving mainly hand muscles. Myopathology descriptions from only 5 patients are available in the literature. We present a comprehensive clinical, pathological and genetic description of 3 patients from 2 families with nephropathic cystinosis. Intrafamiliar variability was detected in one family in which one sibling developed a severe distal myopathy while the other sibling did not show any signs of skeletal muscle involvement. One of the patients was on treatment with Cysteamine for over 12 years but still developed the usual complications of nephropathic cystinosis in his twenties. Novel pathological findings consisting in sarcoplasmic deposits reactive for slow myosin were identified. Three previously known and one novel mutation are reported. Nephropathic cystinosis should be included in the differential diagnosis of distal myopathies in those with early renal failure. Novel clinical and pathological features are reported here contributing to the characterization of the muscle involvement in nephropathic cystinosis.

The unfolding spectrum of inherited distal myopathies

“…A distal myopathy with predominant involvement of the hand muscles can accompany cystinosis, an autosomal recessive lysosomal disorder mainly manifesting with nephropathy and renal failure . It is caused by mutations in the cystinosin gene ( CTNS ), which encodes a lysosomal membrane protein essential for the transport of cystine from the lysosome into the cytoplasm .…”

Clinical and neurophysiological characterization of early neuromuscular involvement in children and adolescents with nephropathic cystinosis

“…Skeletal myopathy is a recognized extra-renal feature of cystinosis, which is speculated to occur due to accumulation of cystine and autophagic vacuoles within perimyseal collagen fibrils in muscles seen on muscle biopsy [12,13]. It was first described in a 20-year-old adult patient with nephropathic cystinosis with progressive symptoms of dysphagia and muscle weakness in upper and lower limbs with a postmortem muscle biopsy showing peri-and endomysial cystine crystals [14].…”

“…White cell cystine levels at time of recruitment were done for three patients with a median of 6 nmol 1/2 cystine/mg protein (range 5. [3][4][5][6][7][8][9][10][11][12][13].…”

Grip Strength in Adults and Children with Cystinosis

“…Since the discovery of cysteamine and the improvement in kidney transplantation outcomes, the survival of cystinosis patients has greatly improved 3 , allowing the development of additional systemic manifestations of the disease 4,5 . Among these, muscle weakness has emerged as a critically important complication [6][7][8] . Muscle weakness prevents patients from completing basic tasks of daily living, negatively affecting patients' quality of life.…”