Lathosterolosis

A number sign (#) is used with this entry because lathosterolosis can be caused by homozygous or compound heterozygous mutation in the SC5DL gene (602286) on chromosome 11q23.

Clinical Features

Brunetti-Pierri et al. (2002) reported the clinical, biochemical, and molecular characterization of a patient with a previously undescribed defect of cholesterol biosynthesis. The female patient presented with a complex phenotype, including multiple congenital anomalies, mental retardation, and liver disease. Physical examination at birth revealed dysmorphic features, including severe microcephaly, receding forehead, anteverted nares, micrognathia, prominent upper lip, highly arched palate, postaxial hexadactyly of the left foot, and syndactyly between the second to fourth toes and between the fifth toe and the extra digit. External genitalia were normal. Severe psychomotor delay became increasingly evident with age. The clinical features somewhat resembled those of Smith-Lemli-Opitz syndrome (270400), which is caused by a defect in cholesterol biosynthesis.

Rossi et al. (2007) provided follow-up on the patient reported by Brunetti-Pierri et al. (2002) and described her affected sib. The sib was a fetus aborted at 21 weeks' gestation following a routine ultrasound that revealed multiple malformations. Postmortem findings included type II Arnold-Chiari malformation, microcephaly, postaxial polydactyly (hands and feet), bilateral clubfeet, and lumbosacral meningocele. A diagnosis of lathosterolosis was suspected on the basis of the pattern of limb and craniofacial anomalies. Molecular analysis in DNA samples obtained from stored pathologic specimens of the SC5DL gene revealed the same mutations identified in her living sister (602286.0001-602286.0002), confirming the diagnosis. The sister had developed bilateral lens opacities at age 6, which subsequently evolved to a total cataract of the right eye, requiring surgery. She had severe cholestasis with liver fibrosis and persistently elevated serum levels of transaminases, gamma-glutamyltransferase, alkaline phosphatase, total and direct bilirubin, and ammonia. Portal hypertension was noted on abdominal Doppler ultrasound at 7 years of age. The girl had experienced 2 pathologic fractures, and DEXA scan at 7.5 years revealed severe generalized osteoporosis. Blood smears revealed anisopoikilocytosis, acanthocytes, schistocytes, large platelets, and vacuolated monocytes. Electron microscopy of cultured fibroblasts showed concentric lamellar inclusion bodies, similar to lysosomal vacuoles visible in fibroblasts from patients with Niemann-Pick type C disease (257220).

Biochemical Features

Plasma and cells of the patient with lathosterolosis reported by Brunetti-Pierri et al. (2002) showed increased levels of lathosterol. Biosynthesis of cholesterol in the patient's fibroblasts was defective, showing a block in the conversion of lathosterol into 7-dehydrocholesterol. Activity of 3-beta-hydroxysteroid-delta-5-desaturase (SC5D), the enzyme involved in this reaction, was deficient in the patient's fibroblasts.

Herman (2003) reviewed the cholesterol biosynthetic pathway and 6 disorders involving enzyme defects in post-squalene cholesterol biosynthesis: Smith-Lemli-Opitz syndrome, desmosterolosis (602398), X-linked dominant chondrodysplasia punctata (CDPX2; 302960), CHILD syndrome (308050), lathosterolosis, and hydrops-ectopic calcification-moth-eaten skeletal dysplasia (HEM; 215140).

Molecular Genetics

In the patient they reported with lathosterolosis, Brunetti-Pierri et al. (2002) identified compound heterozygosity for missense mutations in the SC5DL gene (602286.0001-602286.0002).

In a patient with lathosterolosis, Krakowiak et al. (2003) identified a homozygous missense mutation in the SC5DL gene (602286.0003).

Animal Model

Krakowiak et al. (2003) disrupted the mouse lathosterol 5-desaturase gene (Sc5d). Sc5d -/- pups were stillborn, had elevated lathosterol and decreased cholesterol levels, craniofacial defects including cleft palate and micrognathia, and limb patterning defects. Many of the malformations found in Sc5d -/- mice were consistent with impaired hedgehog signaling and appeared to be a result of decreased cholesterol rather than increased lathosterol.