Pathological Study of the Sural Nerve in Fabry’s Disease

Abstract

A man with Fabry’s disease, who died at 52, suffered from lancinating limb pains between the age of 20 and 27, and from severe arthralgia between 20 and 40. The sural nerve showed a severe loss of fibers (1,614 myelinated fibers/mm²), chiefly affecting the small myelinated fibers. Inclusions of both homogeneous and lamellated appearance were present in the perineurial cells, fibroblasts and vessel walls. Teased fibers displayed moderate remyelination, regeneration and the presence of globular focal myelin thickening. The transient time course of painful manifestations in this case is stressed in view of a possible pathogenesis of pain in Fabry’s disease. It appears that small-fiber neuropathy is not directly related to the occurrence of pain symptoms, since the prevalent loss of small myelinated fibers was seen in the absence of actual pain. The small sensory neurons in the dorsal root ganglia, that are especially affected by lipid accumulation, probably give rise to abnormal discharges producing pain via the prevalence of the small-fiber versus the large-fiber input to the dorsal horn of the spinal cord (gate control theory). Thus pain fits may spontaneously abate, as in our case, if degeneration and loss of the small sensory neurons overstep a critical level.

Nerve biopsy findings in hemizygous and heterozygous patients with Fabry's disease

“…The progression of the neuropathy seemed extremely slow, since only occasional fibres were degenerating. There were a few clusters of regenerating fibres in patient 1, as reported in [7], but not in patient 2. Teased fibre study showed that 5% of the isolated fibres were remyelinated and the rest were normal in patient 1, with no significant changes in patient 2.…”

“…Teased fibre study showed that 5% of the isolated fibres were remyelinated and the rest were normal in patient 1, with no significant changes in patient 2. Some cases showing mild or moderate de-remyelintaed fibres, 12.3% of the isolated fibres in [7] and 4.3% in [15] have been reported in the teased fibre studies. Figure 4 shows the MF histogram.…”

“…Although heterozygous female carriers are either asymptomatic or exhibit milder symptoms, especially corneal opacity [3], some cases with serious neurological complications have also been reported [3,13]. Detailed studies of peripheral nerves in hemizygotes have given somewhat different results [6,7,11,15,16,[20][21][22][23], and to date only one morphometric study is available in a heterozygote [14]. In order to learn more about the nerve lesions of patients with different genotypes of Fabry's disease, we performed a quantitative morphological light-and electron-microscopic study of sural nerve specimens obtained from two patients, one male and one female.…”

“…UA less than 0.4 µm diameter seemed relatively increased, suggesting regenerating sprouts. In hemizygotes the small MF were more reduced in number than the larger ones [7,11,15,[20][21][22], and loss of small neurons in the dorsal root ganglia has also been reported [15] as well as the diminution of UA [15,21]. On the other hand, a few authors have demonstrated the preferential depletion of larger MF [6,16,23], and these patients had a tendency to be of younger age at the biopsy with more preserved MF density.…”

Fabry Disease: A Metabolic Proteinuric Nephropathy

“…Symptoms include episodes of extremity pain or acroparesthesia, gastrointestinal symptoms, hypohidrosis and associated heat sensitivity (Cable et al, 1982;Ries et al, 2005;Rowe et al, 1974) (Table 1). Pain has been linked with small fiber neuropathy (Attal & Bouhassira, 1999) and is thought t o b e c a u s e d b y e i t h e r r e d u c e d p e r f u s i o n o f p e r i p h e r a l n e r v e s o r g l y c o s p h i n g o l i p i d accumulation in neural or perineural cells (Gadoth & Sandbank, 1983;Gemignani et al, 1984). Pain has been described as burning and starts in the hands and feet but can radiate proximally.…”