Generalized anhidrosis with preganglionic sudomotor dysfunction in Fabry disease: a case report

Abstract

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of alpha-galactosidase A (α-Gal A) that catabolizes glycosphingolipids with terminal α-galactosyl groups. The resulting accumulation of glycosphingolipids—particularly globotriaosylceramide (Gb3)—in endothelial cells, podocytes, and other cell types leads to tissue damage that mainly occurs in the kidneys, heart, skin, and nervous system [1]. Severe pain that begins in the distal extremities is the hallmark of early neurological involvement in FD, and decreased sweating (hypohidrosis) is also a common presenting symptom [1, 2]. It is believed that Gb3 deposition is responsible for hypohidrosis by causing sweat gland dysfunction as well as damage to autonomic small fibers [1]. However, dysfunction of the central sweating mechanism in FD has not been reported previously. Here we report a patient with FD who had generalized anhidrosis due to preganglionic sudomotor dysfunction. A 20-year-old man was referred to our hospital because of burning feet and episodic severe radiating pain throughout the body since early childhood. He also suffered from reduced sweating, which led to exercise and heat intolerance. He had no underlying diseases and was not taking any medications. A general examination revealed small purpuric macules and papules in the palms, trunk, and scrotum. There was no family history of unexplained pain or skin lesions. A neurological examination revealed full muscle power and normal light touch, pinprick, vibration, and position sensations. Deep tendon reflexes were normoactive and pathological reflexes were absent. Routine hematological, biochemical, and serological blood findings were unremarkable. We obtained skin biopsy samples from the upper abdomen, which were compatible with angiokeratoma. Nerve conduction studies were normal. Quantitative sensory testing (QST) performed on the left side revealed an increased heat-pain detection threshold in the hand and increased cold and heat-pain detection thresholds in the foot. The amounts of sweat were within the reference range for Koreans during a quantitative sudomotor axon reflex test (QSART) (Fig. 1a) [3]. However, generalized anhidrosis was observed on the thermoregulatory sweat test (TST), in which the oral temperature increased by 1.2 °C (humidity, 35–40%; heating time, 40 min) (Fig. 1b). The heart rate response to deep breathing and blood pressure responses to the Valsalva maneuver were normal. During a tilt-table test there was an excessive increase in the heart rate (from 50 to 95 bpm) within 10 min of standing without orthostatic hypotension. The brain and whole spine magnetic resonance imaging (MRI) findings of the patient were normal. We suspected FD based on the typical clinical presentation, skin lesions, and possible damage to small nerve fibers. We therefore measured the α-Gal A enzyme activity in a dried blood spot (DBS) and plasma. The α-Gal A activity was decreased in the DBS (0.28 μmol/L/h; reference, > 2.35 μmol/L/h) and plasma (0.03 nmol/min/mg protein; reference, 0.5–2.0 nmol/min/mg protein). We also detected an increased plasma concentration of globotriaosylsphingosine (lyso-Gb3) (136 ng/mL; reference, ≤ 1.74 ng/ mL). Subsequently, a missense mutation in the GLA gene, p.Arg227Gln, was identified. We did not find any other manifestations of FD, such as clinical evidence of kidney, heart, eye, or ear involvement. There was no subjective improvement in anhidrosis following 2 years of enzyme replacement * Ki-Jong Park [email protected]