行政院國家科學委員會專題研究計畫成果報告:粒線體疾病疾病表皮神經分佈的變化

粒線體疾病的臨床表現十分多樣化，在神經系 統方面可以出現中樞神經，周邊神經及肌肉的症 狀。粒線體疾病患者的周邊神經病變在臨床及病理 上都有很大的差異性，傳統上評估周邊神經的方法 為使用神經傳導速度及腓腸神經的生檢，前者主要 評估大口徑神經，後者侵襲性大。對於小口徑神經 的病變常須需使用電子顯微鏡。皮膚具有許多感覺 及自主神經的支配，特別可以成為評估小口徑神經 的「窗口」。本計劃利用侵襲性很小的皮膚切片的 方法來評估這群病患表皮中感覺神經的變化。患者 有三人為MELAS 徵候群，一人為MERRF 徵候群，二 人為NARP 徵候群，一人為粒線體肌病變。我們在 小腿外側踝上十公分作皮膚切片，而以免疫組織化 學的方法，利用protein gene product9.5 這種抗體來 標示表皮中的神經末梢，而以每mm 表皮中的表皮 神徑分布來作定量分析。在疾病組其表皮神經密度 為5.33+3.49/mm，控制組為13.73+2.54/mm，疾病 組有顯著減少(p<0.01, Mann-Whitney test)。有 三位患者臨床檢查、神經傳導、感覺閾值均正常， 但表皮神經密度減低。有臨床神經病變的患者有較 明顯的減低，其中最明顯的是一名合併有糖尿病的 病人。表皮神經分佈的變化對於評估粒線體疾病的 周邊神經病變可提供另一種評估的方式。The phenotypes of mitochondrial disease is extremely broad. The clinical manifestation of neuropathy varies from asymptomatic to mild to moderate sensorimotor symptoms. Both axonal and demyelinating polyneuropathy has been described. Traditionally, peripheral neuropathy is studied with electrodiagnostic test and sural nerve biopsy. Few objective measures are available for the assessment of small caliber sensory fibers. Skin has extensive sensory and autonomic innervation(terminal of C and Aδfibers), and represents an attractive site to assess small nerve fibers. In this study we apply skin biosies to examine intracutaneous innervation in patients with mitochondrial diseases. There are 3 patients with mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS), 1 patient with myoclonus epilepsy with ragged red fibers (MERRF), and 2 patients with neurogenic weakness, ataxia, and retinitis pigmentosa (NARP), and one patient with mitochondrial myopathy without known mitochondrial DNA mutation. Skin punches are taken from the lateral aspect of the lag 10 cm above the lateral malleolus, and stained with a monoclonal antibody to neuron-specific ubiquitin hydrolase, PGP9.5. Epidermal innervation was quantified in 5 sections from each specimen and expressed as number of epidermal fibers per mm length of epidermis. There was significant reduction in epidermal innervation of patients with mitochondrial diseases: 5.33 ± 3.49 epidermal nerves/mm in patients compared to 13.73 ± 2.54 epidermal nerves/mm in 20 age- and gender-matched controls ( p