PMC4405612_01
Family pedigree and phenotypical evaluations in the proband. a Family pedigree. The arrow indicates the proband. Three of the proband's sisters were also heterozygous for the SH3TC2 mutation, but only the two affected individuals had compound heterozygous mutations in HEXB and the SH3TC2 mutation. A paternal uncle was diagnosed with amyotrophic lateral sclerosis (ALS). b A photo of the proband showing atrophy and bluish discoloration of the feet. c MR spectroscopy (MRS) of the superior cerebellar vermis showing low N-acetylaspartate (NAA)/creatine ratio, low choline (Cho)/creatine (Cr) ratio, and normal choline/NAA ratio (the arrow indicates the elevated creatine peak). MRS of the same location in the proband's affected sister showed a low choline/creatine ratio. Normal reference ranges were established from five controls. d The vibratory detection threshold (VDT) for the hand, showing increased detection threshold stimulus magnitude just noticeable difference (JND). Shaded circles indicate when a stimulus was detected. No stimulus was administered in trials 2, 4, 12, 14, and 18. The average threshold observed is 19.0 JND (red line), higher than the normative control average of 14.4 JND (blue line). e Hematoxylin and eosin (H+E) staining of the proband's sural nerve demonstrating a reduction of large myelinated nerve fibers; bar 100 mum. f Staining with periodic acid-Schiff (PAS) (pink) and SH3TC2 (brown) in Schwann cells. Arrow indicates miniature onion bulb with multiple Schwann cell nuclei. g Luxol fast staining of a longitudinal section showing evidence of demyelination. h Gomori trichrome staining showing a reduction in myelin staining (red) in the patient as compared to control. i PAS staining in patient's Schwann cells showing positive staining compared to control. j Staining with an antibody for SH3TC2 shows a reduction in staining in the patient compared to control. Bar 50 mum for (f-j)
415_2015_7683_Fig1_HTML.jpg
PMC4405612_01_415_2015_7683_Fig1_HTML.jpg
Fig1
A 46-year-old man had weakness, atrophy, and paresthesia with loss of sensation in his hands and feet for 30 years (Fig. 1a). On examination, he was found to have marked upper and lower extremity weakness and muscle atrophy distally, with the legs more severely affected (Fig. 1b). Autonomic testing (QSWEAT, Heart Rate Response to Deep Breathing, Valsalva, Tilt Table) and quantitative sensory testing (Vibratory Detection Threshold and Cooling Detection Threshold) showed evidence of autonomic dysfunction consistent with a severe small unmyelinated fiber and large myelinated fiber sensory neuropathy (Fig. 1d). MR spectroscopy of the superior cerebellar vermis detected elevated creatine in the proband (Fig. 1c). A sural nerve biopsy from the proband showed evidence of a severe mixed axonal and demyelinating neuropathy (Fig. 1e-i) and a reduction in SH3TC2 immunoreactivity (Fig. 1j).