Deoxysphingolipid precursors indicate abnormal sphingolipid metabolism in individuals with primary and secondary disturbances of serine availability.

Patients with primary serine biosynthetic defects manifest with intellectual disability, microcephaly, ichthyosis, seizures and peripheral neuropathy. The underlying pathogenesis of peripheral neuropathy in these patients has not been elucidated, but could be related to a decrease in the availability of certain classical sphingolipids, or to an increase in atypical sphingolipids. Here, we show that patients with primary serine deficiency have a statistically significant elevation in specific atypical sphingolipids, namely deoxydihydroceramides of 18-22 carbons in acyl length. We also show that patients with aberrant plasma serine and alanine levels secondary to mitochondrial disorders also display peripheral neuropathy along with similar elevations of atypical sphingolipids. We hypothesize that the etiology of peripheral neuropathy in patients with primary mitochondrial disorders is related to this elevation of deoxysphingolipids, in turn caused by increased availability of alanine and decreased availability of serine. These findings could have important therapeutic implications for the management of these patients.

Introduction of sapropterin dihydrochloride as standard of care in patients with phenylketonuria.

Sapropterin dihydrochloride, a synthetic, stable form of the tetrahydrobiopterin cofactor of phenylalanine hydroxylase, has been shown to reduce plasma phenylalanine (Phe) levels in a significant portion of patients with phenylketonuria (PKU). When we undertook introducing this medication to our PKU clinic population, the challenges of recalling and reconnecting with a variably treated and variably compliant patient population became apparent. We offered a trial of sapropterin to all of our clinic patients with PKU. In order to determine responsiveness, we used a two tier dose escalation protocol. After diet records were taken, and baseline plasma Phe levels were established, a 7-day trial of sapropterin at 10mg/kg/day was started. At day 8, plasma phenylalanine levels were measured. Patients were considered to be responders if they had a 30% reduction in plasma Phe. If they did not respond, the dose of sapropterin was increased to 20 mg/kg/day, and levels were rechecked again in 8 days. Patients who were not responders at this time continued sapropterin for a total of 30 days and had Phe levels checked one last time. Patients who were responders and who were on a Phe-restricted diet underwent gradual liberalization of their diet to the maximum tolerated natural protein intake while still maintaining plasma levels in the acceptable treatment range of 120-360 micromol/L. In our population, 36/39 patients with hyperphenylalaninemia (HPA) who were offered a trial of sapropterin elected to start sapropterin. Five of 36 patients were non-adherent with diet records and/or medication doses and we were unable to determine if they were responders. We were unable to categorize 2 of 31 of the patients who completed the trial as responders due to dietary issues, though they were probably responders. Of the 29 patients who completed the sapropterin trial and we could categorize, 18/29 (62%) were determined to be responders. Patients were classified based on their off-diet diagnostic plasma phenylalanine levels as classical PKU (>1200 micromol/L) and variant PKU (>400 and <1200 micromol/L). The group with variant PKU had a 100% response rate, and patients with classical PKU had a 27% response rate. For the patients in the responder group who were on Phe-restricted diet, we were able to liberalize most diets, in two cases to unrestricted protein intake. We also had unexpected beneficial findings in our clinic experience, including positive behavioral improvements in an adult severely affected by untreated PKU. Even in patients who were not considered to be responders, the introduction of sapropterin provided a tool to reconnect with patients and re-introduce beneficial dietary measures.

Semipermeable dressing and transepidermal water loss in premature infants.

Within the first days of life, 10 infants, of 32 weeks' gestational age or less, began 2 weeks of treatment with a semipermeable wound dressing over a small area of skin. The effects of the dressing on transepidermal water loss and cutaneous microflora were evaluated. Transepidermal water loss from the semipermeable dressing-treated skin was significantly less than that from the untreated skin immediately after placement of the dressing (8.1 +/- 1.8 g/m2.h-1 vs 17.7 +/- 3.5 g/m2.h-1, P less than .0001). The normal accelerated skin maturation process that occurs in these infants continued beneath the semipermeable dressing. The number of gram-negative bacilli or other bacteria did not increase beneath the semipermeable dressing beyond that seen on the untreated site. Malassezia furfur was found only on the control site, never beneath the semipermeable dressing. According to results of this preliminary study, a semipermeable dressing can be safely used in premature infants and the use of a semipermeable dressing may decrease the excessive transepidermal water loss associated with prematurity.

Chronic kidney disease in an adult with propionic acidemia.

We report an adult male with classic propionic acidemia (PA) who developed chronic kidney disease in the third decade of his life. This diagnosis was recognized by an increasing serum creatinine and confirmed by reduced glomerular filtration on a (99m)Tc-diethylenetriamine pentaacetate (DTPA) scan. Histopathology of the kidney showed moderate glomerulo- and tubulointerstitial fibrosis with very segmental mesangial IgA deposits. This is the second reported case of kidney disease in an individual with propionic acidemia possibly indicating that chronic kidney disease may be a late-stage complication of propionic acidemia. Additionally, this is the first description of the histopathology of kidney disease in an individual with propionic acidemia. As more cases emerge, the clinical course and spectrum of renal pathology in this disorder will be better defined.

A controlled trial of clobetasol propionate ointment 0.05% in the treatment of experimentally induced Rhus dermatitis.

We studied the effectiveness of clobetasol propionate ointment 0.05% in experimentally induced Rhus dermatitis. Clobetasol rapidly decreased the vesiculation at each treated site, although the effect was most prominent at the site to which clobetasol was applied the earliest, that is, at 12 hours after exposure to Rhus extract. On the basis of this experimental model, clobetasol propionate ointment 0.05% may be effective therapy for naturally occurring Rhus dermatitis.

Comparison of mometasone furoate 0.1% cream and hydrocortisone 1.0% cream in the treatment of childhood atopic dermatitis.

We conducted a 6-week randomized, blinded study that compared mometasone furoate 0.1% cream, applied once daily, and hydrocortisone 1.0% cream, applied twice daily, in 48 children with moderate to severe atopic dermatitis. Mometasone furoate, a moderate-potency steroid, produced significantly greater improvement than the low-potency hydrocortisone used twice daily. The difference in therapeutic response was particularly evident in patients with involvement of more than 25% of their body surface area. Morning plasma cortisol levels were assayed before treatment, after 1 week of therapy, and at the end of the clinical trial. Plasma cortisol levels were transiently suppressed in one child who was treated with hydrocortisone and in none of the children treated with mometasone.

Autosomal dominant multiple cylindromas associated with solitary lung cylindroma.

The occurrence of multiple cutaneous cylindromas constitutes an uncommon autosomal dominant cutaneous disorder whose associations usually are limited to other cutaneous tumors. We report here the first case of a patient with multiple cutaneous cylindromas, who concurrently had a benign lung cylindroma with histologic features identical to her skin lesions. She also had a family history of early death from cardiac disease.