Cerebrotendinous xanthomatosis, sitosterolemia, Smith-Lemli-Opitz syndrome and the seminal contributions of Gerald Salen, MD (1935-2020).

Cerebrotendinous xanthomatosis (CTX), sitosterolemia, and Smith-Lemli Opitz syndrome (SLOS) are rare inborn errors of metabolism. The diagnoses of CTX and sitosterolemia are often delayed for many years because of lack of physician awareness, often resulting in significant and unnecessary progression of disease. CTX may present with chronic diarrhea, juvenile onset cataracts, strikingly large xanthomas, and neurologic disease in the setting of a normal serum cholesterol, but markedly elevated serum or plasma cholestanol levels. These patients have a defect in producing the bile acid chenodoxycholate, and oral chenodeoxycholate therapy is essential for these patients in order to prevent neurologic complications. Sitosterolemia can present with xanthomas, anemia, thrombocytopenia, splenomegaly, very premature heart disease, and serum cholesterol levels that may be normal or elevated, along with marked elevations of plasma ß-sitosterol. These patients have a defect causing overabsorption of ß-sitosterol, and the treatment of choice is oral ezetimibe. SLOS presents with growth delay, intellectual disability, multiple structural anomalies, and low serum cholesterol levels, and the defect is reduced cholesterol production. Treatment consists of dietary cholesterol supplementation and oral bile acid therapy which raises serum cholesterol levels and may improve symptoms. The metabolic and genetic defects in these disorders have been defined. There is no one in our field that has contributed more to the diagnosis and treatment of these disorders than Gerald Salen, MD, who died in late 2020 at 85 years of age. He will be greatly missed by his family, friends, and colleagues from around the world.

[Historical aspects of the Smith-Lemli-Opitz syndrome]. / Historické aspekty Smithovho-Lemliho-Opitzovho syndrómu.

The new malformation syndrome was first described approximately 50 years ago in three unrelated patients in Department of Pediatrics at the University of Wisconsin, Madison, (Smith, Lemli, Opitz 1964). This syndrome was called RSH syndrome after the first 3 patients studied. First Slovak patient with phenotypic features of this new syndrome was described by professor Srsen in 1972. In 1994 Tint from VA Medical Center, E. Orange, New Jersey analyzed plasma sterols of patient with Smith-Lemli-Opitz syndrome and found out that in addition to low plasma cholesterol level, the patient had 1000-fold increase of the plasma level of 7-dehydrocholesterol, the immediate precursor of cholesterol biosynthesis. After this biochemical discovery Smith-Lemli-Opitz syndrome became the metabolic-malformation syndrome with an exactly defined impairment of cholesterol metabolism. The first patient with biochemically proved Smith-Lemli-Opitz syndrome in Slovakia was described by Behulova et al. (1997) in cooperation with Department of Biochemistry and Medical Biotechnology, Federico II University in Naples, Italy. The three years later a screening method UV spectrometry of serum lipids for detection of 7-dehydrocholesterol was established in Department of Biochemistry, University Children´s Hospital in cooperation with the Institute of preventive and clinical medicine in Bratislava (Skodova et al.,2000). First results of molecular analysis of the 7-dehydrocholesterol reductase gene in 10 unrelated Czech and Slovak patients with Smith-Lemli-Opitz syndrome were reported by Kozak et al. (2000). The same year the first prenatal diagnosis of Smith-Lemli-Opitz syndrome by mutation analysis was achieved (Bzduch et al., 2000). Our research activities on this topic drew good response from abroad.

Smith-Lemli-Opitz syndrome diagnosed in a 130-year-old anatomical specimen.

The Museum Vrolik collection of human anatomy comprises 360 recently re-described specimens with congenital anomalies. The external findings in one of these specimens, originally described by Willem Vrolik (1801-1863) 130 years ago, were suggestive of Smith-Lemli-Opitz (SLO) syndrome. Cholesterol synthesis was analyzed in skin biopsies, obtained from the suspected SLO specimen and a control specimen. The cholesterol levels in the SLO specimen and in the control specimen were in the proportion of 1 to 45. This confirms the diagnosis in this specimen which, to our knowledge, represents the oldest known case of SLO syndrome.