Fabry disease: detection of heterozygotes by examination of glycolipids in urinary sediment.

Fabry disease is an X-linked sphingolipid disorder that is manifest clinically as a disease of nerves, kidneys, and blood vessels. Precise identification of Fabry heterozygotes is essential for genetic counseling. Heterozygote detection by enzyme assay does not consistently distinguish them from unaffected females. We describe a method for Fabry heterozygote detection, based on quantitation of urinary sediment glycolipids by high-performance liquid chromatography. In specimens from 12 Fabry heterozygotes, the total glycolipid fraction was increased (10 to 100-fold) and trihexosyl ceramide (CTH) was 2- to 70-fold times normal. Digalactosyl ceramide (Digal-Cer), which is normally present in trace amounts in urine, was also increased. The ratio of CTH and Digal-Cer to hydroxy fatty acid glucosyl ceramide was increased and seemed to be characteristic of Fabry disease. This method provides rapid and accurate detection of Fabry heterozygotes.

Fabry disease: impaired autonomic function.

Previous reports of extensive lipid accumulation within neurons of the autonomic nervous system in Fabry disease suggest an anatomicopathologic basis for the peculiar pain, diminished sweating, and gastrointestinal symptoms experienced in this disorder. To further assess autonomic function in Fabry disease, noninvasive clinical tests were performed on 10 patients. Diminished sweating was found in each; the loss was approximately uniform proximally and distally, suggesting sweat gland dysfunction rather than autonomic neuropathy. Impaired pupillary constriction with pilocarpine, and reduced saliva and tear formation were found in half the patients. Disordered intestinal mobility was demonstrated in the oldest patients. In all cases, the cutaneous flare response to scratch and intradermal histamine was diminished, and pruritus was not experienced. Signs of autonomic dysfunction are present in Fabry disease and correlate with the known lipid deposition in autonomic neurons.

Fabry disease: significance of ultrastructural localization of lipid inclusions in dermal nerves.

An ultrastructural examination of intradermal nerve fibers in Fabry disease revealed signs of lipid accumulation and small unmyelinated nerve fiber degeneration. Many axons were swollen, and their internal organelles were lost. In several damaged axons, dense inclusions, probably lipid, were observed. No lipid inclusions were found in Schwann cells, which may indicate that they utilize different metabolic processes or are impervious to ceramide trihexoside. It is hypothesized that Schwann cells and myelin sheaths act as a metabolic barrier protecting the larger myelinated fibers. Lacking this barrier, the smaller unmyelinated fibers are more susceptible to lipid infiltration. This view may explain the small fiber neuropathy in Fabry disease.

Inborn errors of metabolism.

Inborn errors of metabolism often cause neurological dysfunction. These disorders are most common in childhood, but adult-onset forms with a different clinical presentation are encountered, examples being Pompe disease, Tay-Sachs disease, metachromatic leukodystrophy, Gaucher disease, and Maroteaux-Lamy disease. In the evaluation of a patient with a possible inborn error of metabolism, simple screening tests may aid in the diagnosis and provide direction for more comprehensive laboratory analysis. In most cases, diagnosis can be established without a brain biopsy through biochemical and ultrastructural analysis of peripheral tissues, blood, and urine. New clinical, genetic, and biochemical variants of inherited metabolic disorders are being recognized through wider application of screening tests, improved specificity of laboratory analysis, cell complementation experiments, and the identification of enzyme activator factors. Accurate diagnosis is important for medical management, determining prognosis, and genetic counseling.