This rare disease is transmitted in an autosomal recessive pattern as a result of mutation in CYP27A, which codes for a hydroxylase involved in the metabolic pathway for cholesterol and resulting in an excess of cholestanol. It usually begins in late childhood, with cataracts and xanthomas of tendon sheaths and lungs. As it progresses, difficulty in learning, impairment of retentive memory, and deficits in attention and visuospatial perception (the earliest neurologic manifestations) give way to dementia, ataxic or ataxic-spastic gait, dysarthria and dysphagia, and polyneuropathy. In the late stages (after 5 to 15 years), the patient becomes bedfast and helpless; death occurs at 20 to 30 years of age. In other cases, the clinical course is much more benign. Neuropathologic examination shows masses of crystalline cholesterol in the brainstem and cerebellum and sometimes in the spinal cord, with symmetrical destruction of myelin in the involved areas. The white matter lesions are visible by CT and MRI.
The basic defect is in the synthesis of primary bile acids, leading to an increased hepatic production of cholesterol and cholestanol, which accumulate in brain and tendons. The serum cholesterol levels are normal in most cases but may be as high as 450 mg/dL in others. The tendon xanthomas contain cholesterol, of which 4 to 9 percent is cholestanol (dihydrocholesterol) according to the studies of Moser and colleagues (1984). Cholestanol levels in the serum and red cells are increased. The same elevated levels are found in heterozygotes. The causative mutation is in CYP27A.
Treatment In response to long-term treatment with chenodeoxycholic acid, 750 mg daily, the corticospinal and cerebellar signs and dementia receded in 10 of 17 patients treated and followed by Berginer and coworkers. This drug corrects the defective synthesis of bile acids and restores the low level of chenodeoxycholic acid. Ideally, treatment should begin before the neurologic symptoms appear (Meiner et al). Statin drugs are often added.
In Chap. 33 it was remarked that strokes occur from time to time in children and young adults, often as a result of inherited disorders of the clotting system typified by protein C deficiency, but also of a number of other metabolic derangements, including the mitochondrial disorder MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). Among the many causes, three metabolic diseases must always be considered in the diagnosis of such cases: homocystinuria, Fabry disease, and sulfite oxidase deficiency. Other less-common ones are Tangier disease and familial hypercholesterolemia. Stroke in young persons is also a central feature of the mitochondrial disorder MELAS, discussed further on in this chapter, and of the genetically determined microvasculopathy CADASIL (“Familial Subcortical Infarction” discussed in Chap. 33).