BRF1 mutations in a family with growth failure, markedly delayed bone age, and central nervous system anomalies.

Linear growth failure can be caused by many different genetic abnormalities. In many cases, the genetic defect affects not only the growth plate, causing short stature but also other organs/tissues causing additional clinical abnormalities. A 10-year old boy was evaluated for impaired postnatal linear growth (height 113.3 cm, -4.6 SDS), a bone age that was delayed by 5 years, dysmorphic facies, cognitive impairment, and central nervous system anomalies. His younger brother, presented only with growth failure at 10 months of age. Exome sequencing identified compound heterozygous variants in the gene encoding RNA polymerase III transcription initiation factor 90 kDa subunit (BRF1) in both affected siblings: a missense mutation (c.875 C > G:p.P292R) and a frameshift mutation (c.551delG:p.C184Sfs). The frameshift mutation is expected to lead to nonsense-mediated mRNA decay (NMD) and/or to protein truncation. Expression of BRF1 with the P292R missense mutation failed to rescue yeast lacking BRF1. The findings confirm a previous report showing that biallelic mutations in BRF1 cause cerebellar-facial-dental syndrome. Our findings also help define the growth phenotype, indicating that the linear growth failure can become clinically evident before the neurological abnormalities and that a severely delayed bone age may serve as a diagnostic clue.

Effects of early cysteamine therapy on thyroid function and growth in nephropathic cystinosis.

Primary hypothyroidism is a known complication of nephropathic cystinosis, a lysosomal storage disorder characterized by renal failure as well as deterioration of other organs. The drug cysteamine depletes lysosomes of cystine and helps preserve renal function and enhance growth in cystinosis patients. To determine whether cysteamine also prevents hypothyroidism, we retrospectively divided 101 patients into group A (n = 28; well treated), group B (n = 26; partially treated), and group C (n = 47; poorly treated). Lifetable analysis indicated a significantly higher probability of remaining free of L-T4 replacement in group A vs. group B (P = 0.09) or group C (P = 0.004). Cysteamine therapy also improved mean height z-scores (-2.17 in group A, -3.04 in group B, and -4.07 in group C) and reduced the bone age deficit (i.e. chronological age minus bone age) by 1.5 yr for every 10 yr of previous cysteamine therapy. We conclude that in addition to its other salutary effects, oral cysteamine therapy helps prevent hypothyroidism and enhances growth in patients with nephropathic cystinosis.

The metabolism of fatty acids in human Bietti crystalline dystrophy.

PURPOSE: To investigate the role of abnormal lipid metabolism in Bietti crystalline dystrophy. METHODS: Cultured human lymphocytes and fibroblasts from patients with Bietti crystalline dystrophy (BCD) were incubated in the presence of [(14)C]18:3n-3 or [(14)C]18:2n-6. Incorporation into the cellular lipid pools and further metabolism by desaturation or elongation were monitored by thin-layer chromatography and HPLC. Results were compared with those in normal control subjects and patients with Wolman disease (WD). RESULTS: Pulse-chase experiments with labeled fatty acids in all groups showed that, after 1 hour, radioactivity was largely confined to the triacylglyceride (TG) and choline phosphoglyceride (CPG) pools. However, after several hours, radioactivity was transferred from the TG and CPG pools, some going to the serine and ethanolamine phosphoglyceride (SPG and EPG) pools. Fibroblasts from all groups showed direct transfer of fatty acids (FAs) into CPG and EPG. Incorporation of labeled FAs into the EPG pool paralleled extensive desaturation and elongation of 18:2n-6 to 22:5n-6 and 18:3n-3 to 22:6n-3. Fibroblasts from patients with WD (a lysosomal acid lipase deficiency characterized by excessive lipid accumulation), showed higher incorporation of 18:2n-6 into TGs than did normal or BCD fibroblasts. Conversely, fibroblasts from patients with BCD showed lower conversion of 18:3n-3, but not of 18:2n-6, into polyunsaturated FAs (PUFAs) than those of normal subjects or patients with WD. This was true for total FAs, CPGs, and EPGs. Similar results were found in both fibroblasts and lymphocytes; however, unlike fibroblasts, lymphocytes from normal subjects showed similar levels of incorporation of FAs into EPGs and CPGs. In contrast, incorporation of 18:3n-3 into EPGs was decreased in lymphocytes from patients with BCD. CONCLUSIONS: BCD is characterized by a lower than normal conversion of FA precursors into n-3 PUFA, whereas there is a higher than normal level of n-6 and n-3 FAs incorporation into TGs in cells from patients with WD. These findings raise the possibility that abnormal lipid metabolism associated with BCD is the result of deficient lipid binding, elongation, or desaturation in contrast to the lysosomal acid lipase deficiency found in Wolman disease.

Clinical biochemical and pathologic correlations in Bietti's crystalline dystrophy.

We examined three affected members of a Chinese-American family with Bietti's crystalline retinopathy. The clinical characteristics of a 24-year-old proband are contrasted to the clinical findings of her grandmother, for whom we have 26 years of follow-up data. Lymphocytes and fibroblasts from a skin biopsy of the grandmother contained crystalline lysosomal material, which supports the diagnosis. Biochemical studies of the crystalline lysosomal material failed to identify the stored compounds but did not show them to be cholesterol or cholesterol ester. Finally, histopathologic studies performed for this condition demonstrated advanced panchorioretinal atrophy, with crystals and complex lipid inclusions seen in choroidal fibroblasts.

Purification and spectroscopic properties of pyrene fatty acids.

Pyrene fatty acids are routinely purified by silica based column chromatography and analyzed on thin-layer silica plates (H.-J. Galla et al., Chem. Phys. Lipids, 23 (1979) 239-251). Although pyrene decanoic acid runs as a single spot on thin-layer chromatography (TLC), gas-liquid chromatography (GC) of the methyl ester derivatives of a representative sample revealed four separate peaks with the major component only 92% of the total. High performance reverse phase liquid chromatography (HPLC) was used to purify pyrene decanoic acid and separate the contaminants. After two passes on a C18 reverse phase HPLC column, pyrene decanoic acid is 99.98% pure by GC analysis. Absorption, fluorescence, and NMR spectra were recorded for pyrene decanoic acid and the major impurities. The results indicate that one impurity is a C10 fatty acid with an altered aromatic moiety. Two other impurities are pyrene derivatives but their acyl chains probably are not decanoic acid.

Properties of a specific glycolipid transfer protein from bovine brain.

A transfer protein specific for glycolipids has been isolated from bovine brain. As judged by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis, the protein is 68% pure and has a molecular weight of 20 000. Three different assays were employed to study the protein's specificity and glycolipid binding properties. The protein transferred several different neutral glycosphingolipids and ganglioside GM1 equally well, but failed to accelerate phosphatidylcholine or sphingomyelin intervesicular movement. The protein's ability to interact with glycolipids was strongly influenced by the physical properties of the matrix phospholipid in which the glycolipids reside. Both the phase state of the phospholipid matrix and bilayer curvature affected glycolipid intervesicular transfer rates. Protein binding to phospholipid vesicles containing either tritium-labeled or pyrene-labeled glucosylceramide could not be demonstrated by density gradient centrifugation or fluorescence energy transfer measurements, respectively. A specific association of the transfer protein for pyrene-labeled glucosylceramide was found when the fluorescence emission of the pyrene excimer-to-monomer ratio was measured suggesting that a portion of the fluorescent glycolipid was being sequestered from the phospholipid vesicles and was binding to the freely soluble protein.

Structural characteristics of phospholipid multilamellar liposomes.

The relative proportion of lipid on the external surface of spherical multilamellar vesicles and the aqueous volume trapped within them, can be computed as a function of a liposome's outer radius, interlamellar aqueous spacing, and the number of bilayers. When known experimental data is put into these calculations, the results lead to the conclusion that spontaneously formed liposomes are on the average composed of up to 10 lamellae, whose total thickness is approximately 0.1 micron, and traps an aqueous sphere whose average radius is approximately 0.5 micron. Most of the aqueous medium entrapped within the multi-bilayers is contained in the internal core of the liposome. When assuming spherical liposomes and using percent exposure data, this calculation overestimates the experimentally detected trapped volumes.

Implications of molecular diagnostic testing in families with hereditary pancreatitis.

Hereditary Pancreatitis (HP), is an autosomal dominant trait, which presents with recurrent attacks of abdominal pain, and is the most common cause of chronic relapsing pancreatitis in children. In addition to recurring episodes of intense epigastric pain, patients have nausea, vomiting, and anorexia, and typically show elevated serum amylase levels during the acute episode that can rapidly decline in convalescence. Complications of long-standing disease include features of chronic pancreatitis, such as pancreatic pseudo-cyst, exocrine and endocrine failure, parenchymal calcification, and pancreatic cancer. A large family from Virginia, which was originally studied by Katwinkle and Lapey in 1973, was re-ascertained through a new proband. Linkage studies in this family mapped the gene to the 7q35 region, with similar results being reported simultaneously by two other groups. A pathogenic G to A transition mutation in exon 3 of the cationic trypsinogen (CT) gene, which had previously been mapped to this region, was found both in our family as well as other families from North America. Many other conditions can produce abdominal symptoms that are often mis-attributed to the disease in HP families. An affected member of our family in whom the mutation was confirmed by direct sequencing of exon 3 of the cationic trypsinogen gene requested diagnostic testing on his 4-year-old son because of onset of severe abdominal pain and vomiting. Screening for the mutation in this child did not reveal the pathogenic G to A change. These results prevented unnecessary invasive diagnostic procedures and treatment in this child. The pre-symptomatic testing of high risk individuals could, thus, have a significant impact on the well being of both affected and normal family members.

Partial trisomy 10 mosaicism with cutaneous manifestations: report of a case and review of the literature.

A female infant with partial trisomy 10 mosaicism and hypomelanosis of Ito is presented. Features include a prominent forehead, hypertelorism, large dysplastic ears, prominent nasal root, a cleft lip and alveolar ridge, bilateral metatarsus adductus, and streaks and whorls of hypopigmented skin. The skin findings were diagnostic for hypomelanosis of Ito. A peripheral blood karyotype was normal. Fibroblasts from a junctional skin biopsy revealed mosaicism for partial trisomy of chromosome 10 [46, XX/47, XX, +del(10) (q11.2q23.2)]. The physical findings of this patient are compared to five published cases of complete trisomy 10 mosaicism and 94 cases of isolated trisomy 10p and trisomy 10q.

High-performance liquid chromatography of lipids for the identification of human metabolic disease.

We describe a system for quantitative lipid analysis employing ternary gradient high-performance liquid chromatography with evaporative light scattering detection. This technique was applied to extracts of cultured fibroblasts, cultured lymphocytes, and leukocytes and to liver and spleen biopsy specimens. Separation of nonpolar lipids, glycolipids, phospholipids, and sphingolipids was achieved in a single run. Detection did not depend on the presence of any specific chemical reactions, uv absorption, or fluorescence. The sensitivity of the technique is well below 200 ng for individual lipids, and many individual lipid classes were detected in samples as small as 1 mg of total protein, the yield of a single flask of cultured skin fibroblasts. The characteristic stored lipids cholesterol ester and sphingomyelin were seen in excess in human fibroblast cultures from patients with Wolman's disease and Niemann-Pick disease, respectively. A biopsy spleen sample from a patient with Gaucher's disease showed a large glucosylceramide peak. This system provides a tool for detecting lipids that accumulate in tissues of patients with currently unidentified metabolic storage disorders.

Calorimetric and fluorescence characterization of interactions between cytochrome b5 and phosphatidylcholine bilayers.

The interactions of cytochrome b5 with dimyristoylphosphatidylcholine and dipalmitoylphosphatidylcholine lipid bilayers have been studied with high-sensitivity differential scanning calorimetry and fluorescence spectroscopy. The incorporation of cytochrome b5 into large single lamellar vesicles causes a reduction in the enthalpy change associated with the lipid phase transition. Analysis of the dependence of this enthalpy change on the protein/lipid molar ratio indicates that each cytochrome b5 molecule prevents 14 +/- 1 lipid molecules from participating in the gel to liquid-crystalline transition and that this number is independent of the phospholipid acyl chain length. Resonance energy transfer between the intrinsic tryptophan fluorescence of cytochrome b5 and pyrenedecanoic acid indicates that, in the liquid-crystalline phase, protein and lipid molecules are uniformly distributed within the bilayer plane. In the gel phase, pyrenedecanoic acid partitions into the boundary layer lipid causing a dramatic decrease in the fluorescence intensity of cytochrome b5. The excimer/monomer ratios of pyrenedecanoic acid decrease upon increasing the protein/lipid molar ratio, indicating that the presence of protein molecules within the bilayer slows down the lateral mobility of the lipid probes. The picture that emerges from this set of experiments is that cytochrome b5 perturbs one layer of lipid around the hydrophobic segment of the protein and that this layer is unable to undergo the gel-liquid-crystalline transition, remaining instead in a relatively disordered configuration above and below the transition temperature of the bulk lipid.

Improved renal function in children with cystinosis treated with cysteamine.

BACKGROUND: The lysosomal storage disease cystinosis results in renal failure at approximately 10 years of age. Although oral cysteamine therapy is recognized to preserve kidney function, the extent of renal benefit has not been determined. METHODS: Between 1960 and 1992, we determined 24-hour creatinine clearances in 76 children with cystinosis during 1081 admissions to the National Institutes of Health. Seventeen children were considered to have received adequate treatment with cysteamine, since they had depletion of cystine from leukocytes and began therapy before the age of 2 years; treatment lasted a mean of 7.1 years. Thirty-two children were considered to have received partial treatment, since they had poor compliance with therapy or began treatment after the age of 2; treatment lasted a mean of 4.5 years. Twenty-seven children were followed in the era before cysteamine therapy and thus never received cysteamine. RESULTS: Of the 27 children who never received cysteamine, 16 were followed at the National Institutes of Health until renal failure occurred; their mean (+/- SD) creatinine clearance was 8.0 +/- 4.8 ml per minute per 1.73 m2 of body-surface area at a mean age of 8.3 +/- 1.9 years. Of the 17 children who received adequate treatment, none had renal failure; their mean creatinine clearance was 57 +/- 20 ml per minute per 1.73 m2 at 8.3 +/- 3.8 years of age. The mean creatinine clearance of the children who received partial or adequate treatment with cysteamine increased with age up to the age of five years and then declined linearly with age at a normal rate. For the children who received adequate treatment, the mean creatinine clearance was predicted to reach 0 ml per minute per 1.73 m2 at the age of 74 years, as compared with 20 years of age for the children who received partial treatment. With no therapy, the mean creatinine clearance reaches 0 ml per minute per 1.73 m2 at 10 years of age. CONCLUSIONS: Children with cystinosis who are treated early and adequately with cysteamine have renal function that increases during the first five years of life and then declines at a normal rate. Patients with poorer compliance and those who are treated at an older age do less well.

Mosaic "tetrasomy" 8p: case report and review of the literature.

A male infant presenting with multiple anomalies including a midline cleft palate, anasarca, hepatomegaly, pulmonary edema, agenesis of the corpus collosum, and complex congential cardiac anomalies was found to have mosaicism for an additional chromosome that appeared (following GTG-banding and FISH) to be a monocentric isochromosome of the short arm of chromosome 8 (46,XY/47,XY, +i(8p)). Nine other cases of mosaicism for an additional i(8p) were reviewed. Considerable phenotypic variation was noted. Consistent features were identified including agenesis of the corpus callosum, cardiac malformations, and minor facial dysmorphology. The phenotype of these patients partially overlaps those of trisomy 8 and trisomy 8p. By studying additional individuals with this condition, mosaic tetrasomy 8p may emerge as a recognizable clinical phenotype.

Effect of growth hormone treatment on serum creatinine concentration in patients with cystinosis and chronic renal disease.

Three patients with nephropathic cystinosis and chronic renal disease, treated since early childhood with orally administered cysteamine, had an accelerated rate of rise of serum creatinine values after receiving recombinant human growth hormone. During 18 to 24 months of growth hormone treatment, each patient had a twofold to fourfold increase in growth velocity. The slope of the plot of reciprocal serum creatinine values versus age for each patient after growth hormone treatment was significantly steeper than the pretreatment slope. Growth hormone treatment had no effect on the rate of change of the uncorrected 24-hour renal creatinine clearance. We conclude that these patients gained body size but failed to compensate for their increased creatinine production with an increase in glomerular filtration rate. The result was an accelerated rate of rise of their serum creatinine values, hastening renal transplantation in one patient and the anticipated need for transplantation in another.

Determination of the topography of cytochrome b5 in lipid vesicles by fluorescence quenching.

Cytochrome b5, a protein isolated from the endoplasmic reticulum by detergent extraction, interacts spontaneously with small unilamellar phosphatidylcholine vesicles. When the vesicles are made from 1-palmitoyl-2-oleoylphosphatidylcholine (POPC), the tryptophan fluorescence of the cytochrome is enhanced, and when they are made from 1-palmitoyl-2-(dibromostearoyl) phosphatidylcholine (BRPC), the fluorescence is quenched. A series of BRPC were synthesized with bromine atoms at the 6,7, 9,10, 11,12 or 15,16 positions. The vesicles synthesized from each of these lipids were similar in size to those made from POPC. The relative fluorescence intensities of the cytochrome b5 in POPC and 6,7-, 9,10-, 11,12- and 15,16- BRPC were 100, 19.4, 29.4, 37.1, and 54.0, respectively. These data suggest that the exposed tryptophan(s) is (are) at a depth of 0.7 nm below the surface of the vesicle. Bromine is a collisional quencher; hence, these data may indicate the relative position of the lipid annulus around the protein rather than the depth of the protein below the average vesicle surface. Cytochrome b5 contains three potentially fluorescent tryptophans, and determinations of fluorescent quantum yield indicate all three potentially fluorescent tryptophans, and determinations of fluorescent quantum yield indicate all three are fluorescent with an average quantum yield, when in POPC vesicles, of 0.21. Fluorescence lifetime measurements by the demodulation technique indicated heterogeneity of fluorescence lifetimes in all vesicles. The lifetimes in the BRPC vesicles ranged from 2.0 to 2.4 ns compared to a value of 3.3 ns in POPC.(ABSTRACT TRUNCATED AT 250 WORDS)

Fibrillin-1 (FBN1) mutations in patients with thoracic aortic aneurysms.

BACKGROUND: Mutations in the FBN1 gene are the cause of the Marfan syndrome, an autosomal dominant disorder with skeletal, ocular, and cardiovascular complications. Aneurysms or dissections of the ascending thoracic aorta are the major cardiovascular complications of the disorder. We tested the hypothesis that FBN1 mutations cause thoracic aortic aneurysms or dissections in patients who do not have the Marfan syndrome. METHODS AND RESULTS: The FBN1 gene was screened for mutations by use of genomic DNA from two patients with thoracic aortic aneurysms who did not have the Marfan syndrome. Individual FBN1 exons were amplified with intron-based exon-specific primers; the DNA fragments were screened for mutations using single-stranded conformational polymorphism analysis; and aberrantly migrating bands were sequenced directly. We identified a missense mutation in one patient, D1155N in exon 27. Dermal fibroblasts from the affected individual were used to study the effect of the missense mutation D1155N on fibrillin-1 cellular processing. The mutation decreased the amount of fibrillin-1 deposited into the pericellular matrix. A second putative FBN1 mutation was identified in the second patient, P1837S in exon 44. Although this alteration was not observed in 234 chromosomes from unrelated individuals, the alteration may represent a rare polymorphism. CONCLUSIONS: Results of these studies support the hypothesis that FBN1 mutations cause thoracic aortic aneurysms in patients who do not have the Marfan syndrome. This information is important for understanding the pathogenesis of aortic aneurysms and identification of individuals at risk for developing thoracic aortic aneurysms or dissections.

Redox, transferrin-independent, and receptor-mediated endocytosis iron uptake systems in cultured human fibroblasts.

Sepharose beads bound to 55Fe-transferrin (Tf) were used to evaluate Tf-dependent iron uptake not employing receptor-mediated endocytosis (RME). The iron of 55Fe2-Tf-Sepharose was reduced and taken up by cultured human fibroblasts in a time- and concentration-dependent fashion (Km 7 microM; Vmax 128 pmol/mg/min). This redox system resembled that for Tf-independent iron uptake (Tf-IU, evaluated using 55Fe-citrate) in several ways. 1) NH4Cl did not inhibit iron uptake from 55Fe-citrate and 55Fe2-Tf-Sepharose but did inhibit uptake from 55Fe2-Tf (RME system). 2) Iron uptake and reduction from 55Fe2-Tf-Sepharose and 55Fe-citrate increased with temperature hyperbolically, differing from the sigmoidal curve for RME uptake. 3) The subcellular distributions of iron from 55Fe-citrate and 55Fe2-Tf-Sepharose resembled each other and differed from that for 55Fe2-Tf. 4) The optimal pH for iron reduction and uptake using 55Fe2-Tf-Sepharose or 55Fe-citrate was less than pH 5.5, while that for iron uptake from 55Fe2-Tf was pH 7.4. 5) The uptake and reduction of iron from 55Fe2-Tf-Sepharose was inhibited by ferric citrate and by transition metals. We conclude that both Tf-independent and non-RME, Tf-dependent iron uptake proceed via a common redox system for iron. The mechanisms of cellular iron uptake can be separately evaluated in fibroblasts using 55Fe-citrate, 55Fe2-Tf, and 55Fe2-Tf-Sepharose beads.

Parenchymal organ cystine depletion with long-term cysteamine therapy.

Nephropathic cystinosis is a lysosomal storage disorder characterized by renal failure, multisystem organ damage, and poor growth. Oral cysteamine therapy retards renal deterioration and enhances growth, but parenchymal organ cystine depletion has never been documented. We measured skeletal muscle cystine in 11 cystinosis patients not treated with cysteamine; analysis of their values plus 11 published values showed that muscle cystine increases linearly with age in cystinosis patients (slope, 0.074 nmol half-cystine/mg wet wt/year). In contrast, 15 patients treated for 4 to 11 years with oral cysteamine had a relatively constant muscle cystine content (slope, 0.004 nmol half-cystine/mg wet wt/year). The treated patients' mean muscle cystine, 0.091 +/- 0.064 (SD) nmol half-cystine/mg wet wt, was significantly less (P < 0.001) than that for the 11 youngest untreated patients, 0.754 +/- 0.534 nmol half-cystine/mg wet wt. On postmortem examination, a 9-year-old cystinosis patient treated for 8 years with oral cysteamine had liver, kidney, pancreas, lung, and spleen cystine values 5 to 90 times lower than those of an untreated age-matched control. We conclude that long-term oral cysteamine therapy routinely depletes cystinotic skeletal muscle of cystine; cysteamine is the treatment of choice for the prevention of both renal and nonrenal complications of cystinosis.

Linkage studies in a large kindred with hereditary pancreatitis confirms mapping of the gene to a 16-cM region on 7q.

We report localization of the gene for autosomal dominant hereditary pancreatitis (HP) to a small region of the long arm of chromosome 7 in a large four-generation kindred. Affected family members may first become symptomatic in childhood or even infancy with progression to pancreatic calcification, pseudocyst formation, endocrine and exocrine insufficiency, and even pancreatic cancer in some cases. However, obligate gene carriers may remain virtually symptom free throughout life. HP is the most common cause of childhood pancreatitis in the United States. Gene mapping with microsatellite markers demonstrates that HP is tightly linked to the marker D7S684 (Zmax = 7.0, theta = 0.0). Three obligate recombinants place the HP locus within a 16-cM interval between markers D7S495 and D7S688. This confirms the localization of HP to 7q reported in a separate French kindred (2).

Muscle carnitine repletion by long-term carnitine supplementation in nephropathic cystinosis.

The renal tubular Fanconi syndrome of children with nephropathic cystinosis causes plasma and muscle carnitine depletion. L-Carnitine replacement therapy for up to 18 mo has previously been shown to normalize plasma but not muscle carnitine levels. We treated six cystinosis patients, aged 1 to 4 y, with a mean dosage of 92 mg L-carnitine/kg/d given every 6 h for an average of 62 mo. Despite fractional excretions of free carnitine ranging from 55 to 108%, plasma-free and total carnitine concentrations were maintained at or above normal levels. At the end of the carnitine replacement period, the six children had muscle-free carnitine values ranging from 16.0 to 28.0 nmol/mg noncollagen protein compared with values of 3.0 to 11.4 for cystinosis children not supplemented with carnitine [normal, 22.7 +/- 5.0 (SD) nmol/mg protein]. Total muscle carnitine values were also normalized by L-carnitine replacement. The monthly increase in total body creatinine production, a measure of muscle mass, was higher (p = 0.036) in children with normal plasma free carnitine concentrations (3.4 +/- 0.9 mg/d) than in children with low plasma free carnitine (2.3 +/- 0.7 mg/d). No serious side effects, such as severe diarrhea, were observed. We conclude that oral L-carnitine replacement can normalize muscle carnitine content in children with cystinosis.