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小児脳葉酸欠乏症における脈絡網膜萎縮-予防可能な病気？
[Chorioretinal atrophy in pediatric cerebral folate deficiency-a preventable disease?]
PMID: 32632495 DOI: 10.1007/s00347-020-01126-1.
抄録
脳葉酸欠乏症（CFD）は，放っておくと神経学的な変化と脈絡膜/網膜の大規模な変性を引き起こし，視野と視力が制限される．この記事では，CFDを発症した女性患者の症例を報告する．この患者は，学齢に達する前に自閉症の人格的特徴を発現し，3歳で初めて言葉を話し始めた．6歳の時に右目の視力低下が不明瞭であったため来院した。当時、軽度の両側性末梢脈絡網膜萎縮が認められたが、その後、より顕著になった。さらに，中央部に強調された脈絡網膜萎縮がさらに進行した．両眼の視力は14歳で0.1と低迷するまでに徐々に悪化した。本人の所見の因果関係は長年不明であった。分子遺伝学的検査（変異のないCHM遺伝子）では絨毛色素血症は除外され，オルニチン値の異常から回旋神経萎縮は除外された．アミトコンドリア病の存在は、エクソームシークエンシングによってほぼ完全に除外された。神経筋障害、脳波の変化、自閉症などの非眼症状の発症後、小児科病院での検査診断が強化されました。その結果、脳脊髄液（CSF）中の葉酸代謝物である5-メチルテトラヒドロ葉酸が極めて低いレベルで検出され、CFDと診断されました。その後，葉酸による高用量置換治療を開始した．脳葉酸受容体1に対するFOLR1遺伝子のアパトーシス変異の存在を除外した結果，脳葉酸受容体1に対する高力価ブロッキング自己抗体が原因であることが判明した．
Cerebral folate deficiency (CFD) results in neurological alterations and a massive degeneration of the choroid/retina if left untreated, which limit the visual field and visual acuity. This article reports the case of a female patient with CFD, who developed autistic personal characteristics prior to reaching school age and first started to speak at the age of 3 years. At the age of 6 years she was presented because of unclear reduced visual acuity in the right eye. At that time mild bilateral peripheral chorioretinal atrophy was present, which subsequently became more pronounced. Additionally, a centrally emphasized chorioretinal atrophy further developed. Visual acuity of both eyes progressively deteriorated until stagnating at 0.1 at the age of 14 years. The causal assignment of the findings of the patient was not possible for many years. Choroideremia was excluded by molecular genetic testing (CHM gene with no mutations) and gyrate atrophy was ruled out by a normal ornithine level. The existence of a mitochondrial disease was almost completely excluded by exome sequencing. After the onset of further nonocular symptoms, e.g. neuromuscular disorders, electroencephalograph (EEG) alterations and autistic disorder, intensified laboratory diagnostics were performed in the treating pediatric hospital. Finally, an extremely low level of the folic acid metabolite 5‑methyltetrahydrofolate was detected in the cerebrospinal fluid (CSF) leading to the diagnosis of CFD. High-dose substitution treatment with folic acid was subsequently initiated. After excluding the presence of a pathogenic mutation of the FOLR1 gene for the cerebral folate receptor 1, a high titer blocking autoantibody against cerebral folate receptor 1 was detected as the cause.