Two patients with type I ALD. In .the first patient, non-contrast scans show areas of deceased attenuation in the white matter, typically surrounding the occipital horns (a) and extending to each contrum semiovale. (b). After contrast infusion, bands of enhancement (arrows) are visible at the anterior border of the demyelinating process (c and d). A post-contrast scan of the second patient (•) sh0ws very similar findings, includeing the bands of enhancement (arrowheads).
Type II ALD. Except for some dilatation of the occipital horns, the non-contrast scans do not show convincingly positive findings.
(Di Chiro G et al. A new CT pattern in adrenoleukodystrophy. Radiology 137: 687-692, 1980)
(Addison disease and cerebral sclerosis)
(Bronze Schilder's disease)
(Siemerling- Creutzfeldt 病)
(青銅 Schilder 病)
小児慢性特定疾病 代104 副腎白質ジストロフィー
責任遺伝子：300371 ATP-binding cassette, subfamily D, member 1 (ABCD1)
Abnormality of the cerebral white matter (大脳白質異常) [HP:0002500] 
Abnormality of the skeletal system (骨格異常) [HP:0000924] 
Attention deficit hyperactivity disorder (注意欠陥多動性障害) [HP:0007018] 
Blindness (盲) [HP:0000618] 
Bowel incontinence (遺糞) [HP:0002607] 
Bulbar palsy (球麻痺) [HP:0001283] 
Dementia (認知症) [HP:0000726] 
Elevated circulating long chain fatty acid concentration (長鎖脂肪酸増加) [HP:0003455] 
Hearing impairment (難聴) [HP:0000365] 
Hyperpigmentation of the skin (皮膚高色素) [HP:0000953] 
Hypogonadism (性腺機能低下症) [HP:0000135] 
Impotence (インポテンツ) [HP:0000802] 
Incoordination (協調運動障害) [HP:0002311] 
Limb ataxia (四肢運動失調) [HP:0002070] 
Loss of speech (発語喪失) [HP:0002371] 
Neurodegeneration (神経変性) [HP:0002180] 
Paraparesis (対不全麻痺) [HP:0002385] 
Polyneuropathy (ポリニューロパチー) [HP:0001271] 
Primary adrenal insufficiency (原発性副腎不全) [HP:0008207] 
Progressive (進行性) [HP:0003676]
Psychosis (精神病) [HP:0000709] 
Seizures (けいれん) [HP:0001250] 
Slurred speech (不明瞭発語) [HP:0001350] 
Spastic paraplegia (痙性対麻痺) [HP:0001258] 
Truncal ataxia (体幹失調) [HP:0002078] 
Urinary bladder sphincter dysfunction (膀胱括約筋機能障害) [HP:0002839] 
Urinary incontinence (遺尿) [HP:0000020] 
Visual loss (視力喪失) [HP:0000572] 
X-linked inheritance (X連鎖性遺伝) [HP:0001417]
X-linked recessive inheritance (X連鎖劣性遺伝) [HP:0001419]
けいれん 【神経】神経変性, 進行性
【内分泌】副腎不全 (Addison 病)
小児期 (重症表現型) 〜成人 (限定的表現型)での発症
早期死亡 (2.8 歳)
(女性ヘテロ接合) 進行性対不全麻痺を伴う神経学的異常 (20-30%)
●副腎白質ジストロフィー (Siemerling-Creutzfeldt 病または Schilder 病) は, 進行性脳障害, 副腎不全を生じる最終的に死亡するまれな遺伝性疾患である
ALD は, 髄鞘を進行性に障害し破壊する
髄鞘なしでは, 神経はインパルスを伝達できず, 機能障害が生じる
トランスポーター蛋白と呼ばれる必須タンパクが ALD では欠損している
→食餌の極長鎖脂肪酸 (C25–30) を分解する酵素を運ぶのに必要である
極長鎖脂肪酸が蓄積し, 脳や副腎を障害する (C26: hexacosanoate が最も多い)
● 副腎白質ジストロフィーは髄鞘の成長+/-発達を障害するが, 髄鞘は正常に形成されるが免疫学的機能障害や他の原因で喪失する多発性硬化症などの他の脱髄性疾患とは異なる
症状は4〜10歳で始まり, 獲得した神経学的能力の喪失, けいれん, 運動失調, アジソン病, 視力および聴力機能変性がみられる
→この重症型は Ernst Siemerling および Hans Gerhard Creutzfeldt により最初に記載された
アジソン病は ALD の初発症状でありうるので, 男性患者では極長鎖脂肪酸を測定すべきである
◎主に若年男性を障害するもう一つの型では, 脊髄機能障害がより顕著で, 副腎脊髄ニューロパチーと呼ばれる
MRI は白質異常を示し, いくらか多発性硬化症に似ている
1/42,000 男児 (X連鎖性ALD)
●ALD 遺伝子は酵素ではなく, トランスポーター蛋白ファミリーのメンバーである
ABCD1 遺伝子はペルオキシソーム (脂肪酸をβ酸化する小器官) へ脂肪酸を輸送する蛋白をコードする
●常染色体性副腎白質ジストロフィーは PEX1, PEX5, PEX10, PEX13, PEX26 と連関する
Lorenzo's oil (glyceryl trioleate と glyceryl trierucate の 4:1 混合)+ 低VLCSFA食を, 症状出現前に使用することを推奨 (効果は?だが)
副腎白質ジストロフィーは, 副腎不全と中枢神経系の脱髄を主体とするX連鎖性形式の遺伝性疾患である。小児大脳型, 思春期大脳型, 副腎脊髄ニューロパチー（adrenomyeloneuropathy：AMN）, 成人大脳型, 小脳・脳幹型, アジソン型, 女性発症者などの臨床病型が存在し, 各々の臨床経過, 予後は異なる。生化学的特徴としては, 中枢神経系だけでなく, ほとんどの組織や血漿, 赤血球膜, 白血球などにおいて極長鎖脂肪酸の増加がみられる。
病因遺伝子はABCD1遺伝子であるが, ABCD1遺伝子変異と臨床病型の間に明らかな相関関係は認められず, 遺伝子型から発症年齢あるいはAMNか大脳型かなどの臨床病型を予測することはできない。また, 同一遺伝子異常を有していても異なる表現型を呈する例が多く報告されており, ABCD1遺伝子異常だけではなく, 他に病型を規定する要因（遺伝学的又は環境要因）の存在が想定されている。
典型的な小児大脳型は５～10歳に好発し, 視力･聴力障害, 学業成績低下, 痙性歩行などで発症することが多い。発症後, 比較的急速な進行を呈する。
思春期大脳型（11～21歳発症）は, 小児大脳型と同様の症状を呈するが, やや緩徐に進行する。
成人大脳型（22歳以後の発症）は, 認知症や精神症状で発症し, 比較的急速に進行する。
AMNは, 思春期以降に痙性歩行を主症状に発症し, 陰萎, 排尿障害等を来し, 軽度の感覚障害を伴うことがある。AMNの経過中に, 半数程度は大脳型に移行するとされている。
小脳・脳幹型は, 小脳失調, 痙性不全麻痺を主症状とする。
アジソン型は副腎不全が高度の場合, 嘔吐, 筋力低下, 全身倦怠感, 体重減少に色素沈着を認める。発症は２歳以降, 成人期まで認められる。また, 経過中に神経症状が明らかになる例もあり, 注意を要する。
近年, 小児大脳型において発症後早期の造血細胞移植により, 症状の進行の停止が報告されており, 治療法として期待されている。一方, 進行期での移植例では十分な効果が得られないことが多い。また, 造血細胞移植に関連する合併症（GVHDなど）による重篤例もあり, 適応については十分な検討が必要である。早期の診断と早期の造血細胞移植が予後において極めて重要である。
Lorenzo's oil（オレイン酸：エルカ酸＝４：１）は, 血中の極長鎖脂肪酸（VLCFA）（特に飽和脂肪酸）は正常化するが, 発症した神経症状を抑制する効果は乏しいと考えられる。その他, AMNや女性発症者の痙性対麻痺症状には対症療法として, 抗痙縮薬内服や理学療法を行う。副腎不全に対してはステロイドの補充が行われる（ただし, ステロイドは神経症状には無効である）。
小児大脳型, 成人大脳型は, 無治療の場合, 発症後, 急速に進行し寛解なく, １～２年で臥床状態に至ることが多い。大脳に脱髄病変を認めないAMN症例は緩徐進行性の経過をとり, 生命予後は良好である。ただし, 経過中に成人大脳型に移行し, 急速な進行を認める例があり, 注意が必要である。小脳･脳幹型でも成人大脳型に移行することがある。またアジソン型もAMNや大脳型に進展することがあり, 注意を要する。
未発症男児に関しては, 現時点では病型の予測が不可能であるため, 副腎機能検査と, 大脳型発症が示唆された段階でスムーズな造血細胞移植を実施するために, 発症前の段階から慎重なfollow-up体制をとることが大脳型の予後改善に重要である。
そのためにも, 本症の発端者からの遺伝カウンセリングや家系内の未発症男児への積極的な対応などを, 倫理面に十分な配慮をしながら進めていく必要がある。診断後, 特に３歳から12歳の未発症男児に対しては最低６か月に１回のMRI, 神経生理学的検査（視覚誘発電位及び聴性脳幹反応）, ６か月から１年に１回の神経心理学検査（Wechsler系知能検査他）, 更に12歳以降では１年ごとのMRI検査が必要と考える。いずれかの検査で大脳型の発症が示唆された（所見の進行があった）場合には, 早急に造血細胞移植を検討すべきと思われる。
小児では学習障害, 視力・聴力・認知・書字・発語などの異常が現れる。成人では, 認知症, 高次機能障害（失語, 失行, 失認）などを呈する。
初発症状として多い。視野の狭窄, 斜視, 皮質性の盲などを呈する。
四肢の痙性, 腱反射の亢進, 病的反射陽性で, どの病型においても高頻度に認められる。
無気力, 食欲不振, 体重減少, 色素沈着（皮膚, 歯肉）, 低血圧などを呈する。
C26：0, C25：0, C24：0などの極長鎖脂肪酸の増加を認める。血清スフィンゴミエリン, 血漿総脂質, 赤血球膜脂質などを用いて分析する。極長鎖脂肪酸の蓄積の程度と臨床病型の間には相関性はない。女性保因者の約80％で極長鎖脂肪酸の増加を認める。
小児型ALD 0.0260 ±0.0084 （n＝47）
正常コントロール 0.0056 ±0.0013 （n＝710）
小児大脳型, 思春期大脳型, 成人大脳型では, 大脳白質の脱髄部位に一致して, CTでは低吸収域, MRI T2強調画像では高信号域を認める。病変の分布は後頭葉白質, 頭頂葉白質の側脳室周辺部, 脳梁膨大部が多いが, まれに前頭葉白質から脱髄が始まる例もある。
AMN及び小脳・脳幹型では錐体路, 小脳, 脊髄小脳路の脱髄を主体とする。活動性の脱髄病変のある部位では, ガドリニウムにより造影効果を認める。
臨床的に無症状でも, ACTH高値やrapid ACTH試験で低反応を認めることがある。
病理変化は中枢神経系と副腎であるので, 生前の診断には役立たない。大脳白質の脱髄, グリオーシス, 血管周囲の炎症細胞浸潤が強いことも本疾患の特徴である。副腎では皮質細胞の膨化, 進行期には著明な萎縮を認める。大脳白質マクロファージ, 副腎皮質細胞, 末梢神経シュワン細胞に松の葉様の層状構造物を認める。この構造物は極長鎖脂肪酸を有するコレステロールエステルを含むものと推定されている。
注意欠陥多動障害, 学習障害, 心身症, 視力障害, 難聴, アジソン病, 脳腫瘍, 亜急性硬化性全脳炎（SSPE）, 他の白質ジストロフィー
家族性痙性対麻痺, 多発性硬化症, 精神病, 認知症, 脊髄小脳変性症, アジソン病, 脳腫瘍, 悪性リンパ腫, 他の白質ジストロフィー
(２)血漿, 血清, 赤血球膜のいずれかで極長鎖脂肪酸値が高値。
(３)頭部MRI, 神経生理学的検査, 副腎機能検査のいずれかで異常を認める。
③診断基準(１)と(３)を満たす女性で, 家族内に発症者又は保因者がいる, あるいは極長鎖
＜小児慢性特定疾病 代104 副腎白質ジストロフィー＞
副腎白質ジストロフィー(adrenoleukodystrophy; ALD)は中枢神経の白質と副腎の障害を特徴とするX連鎖性の遺伝性疾患で, ３～10歳で発症して大脳半球の広範な進行性脱髄と副腎機能不全を特徴とする小児大脳型や20歳以降に痙性歩行で発症するadrenomyeloneuropathy (AMN), 成人で性格変化, 知能低下, 精神症状で発症する成人大脳型に, 副腎不全症状のみのタイプなど多彩な臨床型を有している。病因はXq28に存在するABCD1遺伝子異常による。しかしその病態についてはほとんど解明されておらず, 多彩な臨床型も遺伝子変異とは相関が無く, 脱髄の発症機序や極長鎖脂肪酸蓄積の病態への関与も未解明である。また大脳型の唯一の治療法は発症早期の造血細胞移植である。
1) 小児大脳型 (CCALD) ：3～10歳に視力や聴力の異常，行動異常や成績低下，歩行障害，けいれん等で発症し，症状の広がりから急速な進行を認め，数年で寝たきりの経過をとることが多い。
4) 成人大脳型（ACALD）：精神症状, 行動異常, 認知機能低下等で初発し, 比較的急速な進行を呈する。
(1) 以下に示す各臨床型の診断ポイントをもとに, ALDを疑い, 血中極長鎖脂肪酸を測定する。
1) 小児および思春期大脳型：途中から気づく斜視や, 「見えにくそう」, 「聞こえにくそう」な様子から眼科や耳鼻科を受診後に経過観察されている症例, 学校等にて落ち着きのなさや行動異常, 成績低下, 書字やしゃべり方の異常からADHDや学習困難児として対応されている症例もみられる。いずれもけいれんの発症や症状の進行や広がりにより専門医等を受診して, 脳MRI検査にてALDが疑われることが多い。それ以外にも年少児も含めた歩行障害やけいれんを初発症状として認める症例も散見される。好発年齢としては7歳を頂点に, 多くは3歳から15歳くらいまでに発症する。
2) AMN：つっぱったような歩行障害（痙性対麻痺）がゆっくりと現れ, 排尿障害（尿が漏れる）, 陰萎（インポテンツ）などの自律神経障害も加わる。腫瘍や損傷とともに脊髄小脳変性症の鑑別としても重要である。
3) 成人大脳型：成人期以降に性格の変化, 知能低下, 精神病様症状などで発病するため, 認知症や精神疾患の鑑別として重要である。
4) アジソン型：2歳以降から成人期にかけて非特異的な症状である易疲労感, 全身倦怠感, 脱力感, 筋力低下, 体重減少, 低血圧などで発症する。また食欲不振や悪心･嘔吐, 下痢などの消化器症状, 精神症状（無気力, 不安, うつ）など様々な症状も訴える。鑑別として重要な症状である色素沈着は皮膚, 肘や膝などの関節部, 爪床, 口腔内にみられる。
5) 女性保因者：一部の女性保因者では加齢に伴い, AMN類似の症状を来すことがある。
(2) 男性 ALD患者では上記の臨床所見, 大脳型では脳MRIに, 血中極長鎖脂肪酸の増加を認めれば診断は確定的である。一方, 女性保因者では極長鎖脂肪酸は増加する傾向にあるものの, その値にはかなりの幅があり, 確定診断にはABCD1遺伝子変異の確認が必要である。
大脳型では無治療の場合, 2年以内に嚥下障害，寝たきりになる症例が多いが, 進行が緩やかな例もある。AMNでは一般に緩やかに進行するが, 大脳型に移行して急速な悪化をきたす例が存在する。小脳・脳幹型も大脳型に, アジソン型でもAMNや大脳型に進展することがあるので，注意を要する。
ALD患者では半数以上は成人期以降に発症する。小児期に発症前診断された患者では, 現時点では病型予測は不可能であり, 成人期以降もMRI検査や副腎機能評価, 神経内科などでの定期的なフォローアップが重要である。
(コメント) VLCFA 酸化障害 (おそらく lignoceroyl-CoA ligase 欠乏)
(参照) *601081 Adrenoleukodystrophy-related gene
(責任遺伝子) *300371 ATP-binding cassette, subfamily D, member 1 (ABCD1)
(1) Adrenoleukodystrophy (300100)
.0001 Adrenoleukodystrophy [ABCD1, GLU291LYS] (dbSNP:rs128624213) (RCV000012044) (Cartier et al. 1993)
.0002 Adrenoleukodystrophy [ABCD1, PRO484ARG] (dbSNP:rs128624214) (RCV000012045) (Berger et al. 1994)
.0003 Adrenoleukodystrophy [ABCD1, IVS6AS, A-G, -2, FS546TER] (RCV000012046) (Kemp et al. 1995)
.0004 Adrenoleukodystrophy [ABCD1, IVS8AS, G-A, -10, 8-BP INS, FS638TER] (RCV000012047) (Kemp et al. 1995)
.0005 Adrenomyeloneuropathy [ABCD1, ARG389GLY] (dbSNP:rs128624215) (RCV000012048) (Krasemann et al. 1996)
.0006 Adrenoleukodystrophy [ABCD1, ASN148SER] (dbSNP:rs128624216) (RCV000012049) (Fuchs et al. 1994)
.0007 Adrenoleukodystrophy [ABCD1, TYR174ASP] (dbSNP:rs128624217) (RCV000012050) (Fuchs et al. 1994)
.0008 Adrenoleukodystrophy [ABCD1, GLY266ARG] (dbSNP:rs128624218) (RCV000012051) (Fuchs et al. 1994)
.0009 Adrenoleukodystrophy [ABCD1, ARG401GLN] (dbSNP:rs128624219) (RCV000012052) (Fuchs et al. 1994)
.0010 Adrenoleukodystrophy [ABCD1, ARG418TRP] (dbSNP:rs128624220) (RCV000012053) (Fuchs et al. 1994)
.0011 Adrenomyeloneuropathy [ABCD1, ARG464TER] (dbSNP:rs128624221) (RCV000012054) (Fanen et al.1994)
.0012 Adrenoleukodystrophy [ABCD1, 2-BP DEL, FS, TER] (dbSNP:rs387906494) (RCV000012055) (Barcelo et al. 1994)
.0013 Adrenoleukodystrophy [ABCD1, GLU477TER] (dbSNP:rs128624222) (RCV000012056) (Fuchs et al. 1994)
.0014 Adrenoleukodystrophy [ABCD1, SER515PHE] (dbSNP:rs128624223) (RCV000012057) (Fuchs et al. 1994)
.0015 Adrenoleukodystrophy [ABCD1, 1-BP DEL, 1937C, FS557TER] (dbSNP:rs387906495) (RCV000012058) (Fanen et al. 1994)
.0016 Adrenomyeloneuropathy [ABCD1, ARG518TRP] (dbSNP:rs128624224) (RCV000012059) (Fanen et al. 1994)
.0017 Adrenomyeloneuropathy [ABCD1, IVS6DS, G-A, +1] (RCV000012060) (Fanen et al. 1994
.0018 Adrenoleukodystrophy [ABCD1, 2-BP DEL, FS599TER] (RCV000012061) (Fanen et al. 1994)
.0021 Adrenomyeloneuropathy [ABCD1, ARG617HIS] (dbSNP:rs11146842) (RCV000012064) (Fanen et al. 1994)
.0022 Adrenoleukodystrophy [ABCD1, ARG617CYS] (dbSNP:rs4010613) (RCV000012065) (Fanen et al. 1994)
.0023 Adrenoleukodystrophy [ABCD1, 3-BP DEL, 1258GAG] (dbSNP:rs387906496) (RCV000012066) (Kano et al. 1998)
.0024 Adrenoleukodystrophy [ABCD1, IVS8DS, G-A, +1] (RCV000012067) (Guimaraes et al. 2001)
.0025 Adrenoleukodystrophy [ABCD1, IVS1DS, G-A, -1] (v) (Guimaraes et al. 2001)
.0026 Adrenoleukodystrophy [ABCD1, 26-BP DEL, NT369] (dbSNP:rs387906497) (RCV000012069) (O'Neill et al. 2001)
(2) Addison disease
.0019 Addison disease [ABCD1, SER606LEU] (dbSNP:rs128624225) (RCV000012062...) (Fanen et al. 1994)
.0020 Addison disease [ABCD1, 1-BP DEL, 2204G, FS635TER] (RCV000012063) (Fanen et al. 1994)
*ABCD1: ATP-binding cassette, sub-family D (ALD), member 1; (745 amino acids)
・ヌクレオチド結合襞は ATPase 活性を伴う ATP 結合サブユニットとして作用する
・ATP-binding cassette (ABC) トランスポーターのスーパーファミリーのメンバーである
・ABC タンパクは, いろんな分子を細胞外および細胞内膜を通して輸送する
・ABC 遺伝子は7つのサブファミリーに分類される (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White)
・ABCD1タンパクは ALD サブファミリーのメンバーで, 小器官での脂肪酸+/-fatty acyl-CoAsのペルオキシソーム輸入に関与する
全ての知られているペルオキシソーム ABC トランスポーターは, 半トランスポーターで, 機能的ホモダイマーまたはヘテロダイマートランスポーターを形成するためパートナーとなる半トランスポーター分子を必要とする
A number sign (#) is used with this entry because of evidence that adrenoleukodystrophy and adrenomyeloneuropathy are caused by mutation in the ABCD1 gene (300371) on chromosome Xq21.
●副腎白質ジストロフィー は、X連鎖性疾患で、ABCD1 遺伝子変異に二次性である
→ペルオキシソームβ酸化の明らかな障害と、身体の全組織での飽和極長鎖脂肪酸 (VLCFA) の蓄積となる
本疾患の症状は、主に副腎皮質、中枢神経ミエリンおよび精巣の Leydig 細胞で生じる
●ABCD1 は、CFTR と MDR タンパクなどと同じトランスポータータンパクのカテゴリーである ATPase binding cassette タンパクである
●X-ALDが脂肪蓄積疾患であり、VLCFAs の分解能の障害で、ペルオキシソーム病である証明は Moser (1997)によりレビューされた
●Moser et al. (2005) は ALD の臨床的レビューを提供した
● 副腎白質ジストロフィー は、いろんな年齢で生じえ、神経学的所見の存在とタイプによる異なる症状をもつ
●Moser et al. (2000) は、7つの表現型があると述べた
→小児脳型、副腎脊髄ニューロパチー (AMN)型, 成人脳型、思春期型、神経病のない副腎不全型、無症状型、およびヘテロ接合体
Davis et al. (1979) observed a family with 4 cases of adrenoleukodystrophy and 1 of adrenomyeloneuropathy, suggesting the fundamental identity of the 2 disorders. The patient with adrenomyeloneuropathy was well until age 21 years when he developed spastic paraparesis. He subsequently fathered 2 daughters and a stillborn child. He was 41 years old at the time of study and showed no clinical manifestations of adrenal insufficiency. A brother of his developed paraparesis at age 13 and progressed to death at age 19. A nephew became ill at age 4 and died at age 7. Autopsy showed atrophic adrenals although no clinical signs of adrenal insufficiency were observed.
O'Neill et al. (1982) studied a kindred in which 14 members were affected with a variable combination of neurologic and adrenal manifestations. Abnormality was identified by increased content of C(26:0) fatty acid (hexacosanoic acid) in cultured skin fibroblasts and abnormal C26/C22 fatty acid ratios. The latter ratios were not proportional to severity of disease, duration, or character of the neurologic syndrome. In the family reported by O'Neill et al. (1980, 1982), clinically apparent Addison disease without neurologic involvement was the expression of adrenoleukodystrophy in males, and spastic paraplegia and sphincter disturbances occurred in female carriers.
Berg et al. (1989) described phenotypic features of a 362-member kindred spanning 6 generations. They observed clustering of phenotypes within individual sibships of the pedigree.
Willems et al. (1990) showed that patients with ALD and AMN in the same pedigree had identical haplotypes, demonstrating that they are not caused by different allelic mutations.
Holmberg et al. (1991) described a remarkable family in Sweden in which there was Addison disease in a 13-year-old boy, adrenomyeloneuropathy in a 58-year-old man, and spastic paraparesis and peripheral neuropathy in at least 3 heterozygous females, including the 85-year-old mother of the man with AMN.
Sobue et al. (1994) described considerable phenotypic heterogeneity between 2 proven monozygotic twins, both of whom had myeloneuropathy. Extensive demyelination in the brain was only prominent in the older twin, while adrenal insufficiency was prominent in the younger twin. They suggested that nongenetic factors were important determinants of the phenotypic variation of the adrenoleukodystrophy gene. Korenke et al. (1996) and Di Rocco et al. (2001) also reported pairs of identical male twins with different clinical expressions of ALD. Wilichowski et al. (1998)found no difference in mitochondrial DNA in the twins reported by Korenke et al. (1996). Di Rocco et al. (2001) stated that the discordant adrenoleukodystrophy phenotypes in 3 pairs of monozygotic twins indicated that modifier genes were not involved in determining the occurrence of CNS degeneration. They suggested that identifying environmental factors could be important for effectively preventing CNS degeneration in this disorder.
By neuropsychologic testing, Cox et al. (2006) found normal cognitive function in 48 of 52 neurologically asymptomatic boys with ALD (mean age, 6.7 years). All of the patients had normal brain MRI studies. However, there was a negative correlation between age and visual perception as well as age and visuomotor skills. Cox et al. (2006) concluded that a subset of patients with the childhood form of ALD have normal neurodevelopment despite an inherent defect in the ABCD1 gene.
Childhood Cerebral Adrenoleukodystrophy
The classic presentation of childhood cerebral ALD has been analyzed in several large series (Schaumburg et al., 1975; Aubourg et al., 1982). This is the form of the illness that was originally described by Siemerling and Creutzfeldt (1923) and, until it was possible to make the biochemical diagnosis, it was the only form of the disease recognized as adrenoleukodystrophy. It is a rapidly progressive demyelinating condition affecting the cerebral white matter. It is by definition confined to boys who develop cerebral involvement before the age of 10 years. The boys are normal at birth and have unremarkable development. The mean age of onset is approximately 7 years.
The disease usually manifests itself early with behavioral manifestations including inattention, hyperactivity, and emotional lability. It often becomes apparent through school difficulties. It progresses into visual symptoms, auditory processing difficulties, and motor incoordination. Once the neurologic manifestations appear, progression of the illness is tragically rapid and the child is often in a vegetative state within 1 to 2 years.
Magnetic resonance imaging is often the first diagnostic study and shows a characteristic pattern of symmetric involvement of the posterior parietooccipital white matter in 85% of patients, frontal involvement in 10%, and an asymmetric pattern in the rest.
Budka et al. (1976) reported a case they interpreted as an adult variant of adrenoleukodystrophy. At the time, a geneticist could raise the possibility of this form being the consequence of an allelic mutation, but phenotypic variability within families has subsequently been demonstrated. The neurologic picture was dominated by spastic paraplegia. Both clinically and pathologically, absence of diffuse cerebral involvement was noteworthy. The endocrinologic disorder was the particularly striking feature.
Griffin et al. (1977) and Schaumburg et al. (1977) described a variant that they called adrenomyeloneuropathy. Hypogonadism was present in all cases appropriately studied. Adrenal insufficiency began in childhood and progressive spastic paraparesis in the third decade. Neurologic features included peripheral neuropathy, impotence, and sphincter disturbances.
O'Neill et al. (1985) found biochemical characteristics of ALD in 2 brothers with spastic paraplegia of onset at age 40 and 50 years. Further study in the family revealed 2 nephews who were also affected as well as asymptomatic carriers in a typical X-linked pedigree pattern. None had symptoms of adrenal insufficiency. Cotrufo et al. (1987) reported the remarkable cases of an uncle and nephew who were completely asymptomatic at ages 25 and 10, respectively, but who showed levels of very long chain fatty acids in plasma consistent with the ALD hemizygote state. Both were found to have adrenocortical insufficiency as evidenced by compensatory high ACTH release.
Uyama et al. (1993) described a man who had presenile onset (at age 51 years) of the cerebral form of ALD. The first manifestation was difficulty in recalling where he had placed things. Shortly thereafter, he had problems operating farm machinery and gradually developed difficulty seeing clearly and writing at normal speeds. He could dress himself but often put garments on backward or inside out. He later developed Balint syndrome and dementia. (Balint syndrome is an acquired visuospatial disorder characterized by psychic paralysis of visual fixation, optic ataxia, and disturbance of visual attention with relatively intact vision (Hecaen and De Ajuriaguerra, 1954).) MRI demonstrated demyelinating lesions in the bilateral posterior parietooccipital white matter involving the splenium of the corpus callosum. The patient could not move his eyes on command or follow a moving object. He had difficulty in maintaining central fixation. Optic ataxia was also shown by frequent errors when he attempted to grasp an object at which he was looking. The patient was bedridden by age 54 and died at age 55. Tests of adrenal function yielded normal results. Ratios of C26:0 to C22:0 in plasma and in erythrocyte membranes established the diagnosis of ALD in the proband and demonstrated that his mother was a heterozygote.
Van Geel et al. (2001) studied the evolution of the disease in adults. They studied 129 men retrospectively, with a mean follow-up period of 10.1 +/- 5.0 years. Among 32 neurologically asymptomatic patients, 16 (50%) developed some neurologic involvement. Among 68 men with AMN without cerebral involvement, 13 (19%) developed clinically apparent cerebral demyelination. There was a high risk for adult neurologically asymptomatic patients to develop neurologic deficits and for AMN patients to develop cerebral demyelination. This had implications for the phenotype classification, search for modifying factors, and the development and evaluation of new therapies.
Eichler et al. (2007) reviewed serial brain MRI scans of 56 adult patients with ALD and white matter abnormalities. Forty-two (75%) of these patients had corticospinal tract involvement, and 21 (50%) of the 42 showed lesion progression over a 3 to 5-year period. Disease progression was slower in adults compared to that previously observed in affected children. Only 3 adult patients showed isolated lesions in the genu or the splenium, all of which developed in childhood or adolescence. The findings suggested that progressive inflammatory demyelination can occur along with the known axonopathy of adulthood. Eichler et al. (2007) suggested that the vulnerability of specific fiber tracts in ALD changes with age.
Addison disease in young males should prompt consideration of ALD as the underlying abnormality. See also Sadeghi-Nejad and Senior (1990).Laureti et al. (1996) performed biochemical analysis of very long chain fatty acids in 14 male patients (age ranging from 12-45 years at diagnosis) previously diagnosed as having primary idiopathic adrenocortical insufficiency. In 5 of the 14 patients, elevated levels of very long chain fatty acids (VLCFA) were found in plasma; none had adrenocortical antibodies. By electrophysiologic tests and magnetic resonance imaging, it was determined that 2 had cerebral ALD, 1 had adrenomyeloneuropathy with cerebral involvement, and 2 had preclinical AMN.
Since the adrenal insufficiency may long precede neurologic manifestations and perhaps may occur alone, caution must be exercised in the interpretation of isolated X-linked Addison disease as a separate entity. Of course, autopsy-confirmed adrenal hypoplasia (300200) is a well-established entity.
The achalasia-Addisonian syndrome (231550), which appears to be autosomal recessive, is another example of combined adrenal and neurologic (autonomic) involvement.
The postperfusion syndrome is an uncommon event following open-heart surgery with extracorporeal circulation. It is associated with a young age at surgery (less than 1 year) and bypass lasting longer than 60 minutes. Luciani et al. (1997) observed the syndrome in an 18-year-old man who underwent transpulmonary patch repair of a ventricular septal defect with cardiopulmonary bypass for 50 minutes. Preoperatively, the patient exhibited a slight gait disorder and unremarkable EEG and laboratory findings. Twelve hours after surgery he developed hypotension and circulatory collapse. This was treated successfully, but 10 days after discharge the patient was admitted with findings suggesting Addison disease. He showed a worsening disturbance of gait, with ataxia and EEG abnormalities. The diagnosis of adrenoleukodystrophy was supported by MRI of the head and confirmed by increased plasma levels of very long chain saturated fatty acids. Thus, Luciani et al. (1997) concluded that this was a case of Addisonian crisis precipitated by surgery in a patient with previously unrecognized AMD.
Women who are carriers for the condition may develop spastic paraparesis with bowel and bladder difficulties. This appears to be partially a function of age.
Heffungs et al. (1980) observed cerebral sclerosis and Addison disease in a previously healthy 14-year-old sister of an affected boy. They suggested that this was the first documented example of adrenoleukodystrophy in a heterozygote. Several other unusual examples have been published.
Also see O'Neill et al. (1982). The patient reported by Noetzel et al. (1987) illustrates further the occurrence of a chronic nonprogressive spinal cord syndrome in women heterozygous for ALD.
Hershkovitz et al. (2002) reported an 8.5-year-old girl who presented with declining school performance and diffuse frontal white matter demyelination. She was known to be at risk for heterozygosity because 2 maternal uncles had ALD. Levels of very long chain fatty acids were elevated. DNA analysis of the patient and her mother showed a cytosine insertion in codon 515 (515insC) of the ABCD1 gene, resulting in a frameshift after amino acid 171 (tyrosine). Immunocytochemical studies showed that ALDP reactivity was lacking in 99% of the fibroblasts analyzed. Cytogenetic analysis showed a deletion at Xq27.2-qter. Both parents were normal. She underwent bone marrow transplantation from a normal sister and at 18 months was stable. Hershkovitz et al. (2002) recommended that cytogenetic studies be performed in the 1% of heterozygotes who show evidence of cerebral involvement.
Jung et al. (2007) reported 2 unrelated women with heterozygous mutations in the ABCD1 gene. The first patient was diagnosed at age 8 years with manic-hebephrenic disorder and subsequent psychotic episodes. She had spastic paraparesis at age 25 and developed cognitive deficits, cerebellar signs, and more severe spastic paraparesis at age 45. She died of pneumonia at age 52. Her brother had Addison disease at age 47, and later developed spastic paraparesis and polyneuropathy. The second patient developed inability to run at age 35 years, 1 year after her son died of ALD. She was wheelchair-bound by age 48. Later features included bilateral visual loss and mild polyneuropathy. She was cognitively intact.
Kobayashi et al. (1986) described 2 adult male first cousins with spinocerebellar degeneration manifested by progressive limb and truncal ataxia, slurred speech, and spasticity of the limbs. Brain CT scans showed atrophy of the pons and cerebellum. Very long chain fatty acids were elevated in the plasma and red cell membranes of the affected patients and were increased to intermediate levels in the female carriers.
An important observation was that of Igarashi et al. (1976). They found that cholesterol esters in the brain and adrenals of these patients had an unusually high proportion of fatty acids with a chain length of 24-30 carbon atoms, rather than the usual length of less than 20. This might interfere with myelin formation in the CNS and steroidogenesis in the adrenal.
Biochemical studies of cerebral white matter showed increased amounts of long chain saturated fatty acids in cholesterol esters.
ALD is characterized by the accumulation of unbranched saturated fatty acids with a chain length of 24 to 30 carbons, particularly hexacosanoate (C26), in the cholesterol esters of brain white matter and in adrenal cortex and in certain sphingolipids of brain. Accumulation also occurs in plasma-cultured skin fibroblasts and this fact can be used for diagnosis (including prenatal diagnosis) and for the study of the disease's basic mechanisms (Moser et al., 1980).
It appears that the defect is in the catabolism of the very long chain fatty acids (see 603314) themselves. A parallel to Refsum disease (266500) in which a fatty acid of dietary origin accumulates because of deficiency of an enzyme for its catabolism is suggested by the finding that the accumulating long chain fatty acids are, at least in part, of exogenous origin (Moser, 1980). This finding and analogy suggest that dietary modification may be beneficial in ALD.
Moser et al. (1981) investigated a possible defect in a peroxisomal beta-oxidation system.
The work of Hashmi et al. (1986) and of Singh et al. (1988) suggested that the basic defect in X-linked ALD is deficient activity of lignoceroyl-CoA ligase. Singh et al. (1988) and Lazo et al. (1988) presented data demonstrating that the accumulation of very long chain fatty acids in ALD is the result of deficient peroxisomal lignoceroyl-CoA ligase activity. It had previously been thought that the same ligase was responsible for the activation of C16:0 (palmitic acid) and C24:0 (lignoceric acid). Later data indicated that they are separate enzymes. Wanders et al. (1987, 1988) had interpreted their results as indicating that the basic defect in X-linked ALD resides in peroxisomal very long chain fatty acyl-CoA synthetase. This enzyme is present not only in peroxisomes but also in microsomes.
The identification of the genetic defect and protein abnormality in ALD has resulted, however, in different conclusions. The defect is not in an enzyme, but in a protein, ABCD1, that has a role in peroxisomal beta-oxidation. It has been suggested that the protein has a role in transport.
Beta-oxidation of fatty acids occurs through a carnitine-dependent pathway in the mitochondria and a carnitine-independent pathway in the peroxisomes. In cell cultures and mouse tissue, McGuinness et al. (2003) showed that the ALDP protein transporter may facilitate an interaction between peroxisomes and mitochondria, which is disturbed in X-linked ALD.
Stradomska and Tylki-Szymanska (2001) described the results of measuring serum very long chain fatty acid concentrations in 59 females of various ages with heightened risk of carrier status for ALD. In female carriers aged 22 to 50 years, they found serum VLCFA concentrations in a range characteristic of heterozygotes; VLCFA levels were normal in female carriers aged 55 to 64 years. In women aged 37 to 50 years in whom repeat studies of VLCFA concentrations were performed after 5 years, a reduction in VLCFA was observed. Stradomska and Tylki-Szymanska (2001) suggested that the results point to a reduction of serum VLCFA concentrations as X-ALD heterozygotes age.
Fanconi et al. (1963) suggested X-linked recessive inheritance of a syndrome of Addison disease and cerebral sclerosis. All cases had been male, and in many instances a brother and/or a maternal uncle of the proband has been similarly affected.
Using content of C26 fatty acids in cultured fibroblasts, Migeon et al. (1981) demonstrated two types of clones in heterozygotes, thus corroborating X-linkage and demonstrating lyonization of the ALD locus. The presence of more mutant than wildtype clones in cultures from most heterozygotes suggested a proliferative advantage of the mutant cells. This advantage appears to exist in vivo also because most heterozygotes showed increased levels of fatty acids in plasma and, in 1 family, women heterozygous for both ALD and G6PD showed an excess of G6PD blood cells of the A (rather than B) type, which was in coupling with the mutant gene. (In Lesch-Nyhan syndrome (308000), it is the wildtype red cell precursors that enjoy a selective advantage so that in heterozygotes the levels of HPRT in red cells are normal.)
Using the probe M27-beta, Watkiss et al. (1993) found no evidence for skewed X-inactivation in 12 female carriers of ALD. The probe M27-beta detects locus DXS225, which contains a highly polymorphic VNTR sequence. In addition, the locus contains MspI sites that are methylated on the active X chromosome but unmethylated on the inactive X chromosome. Because such sites are vulnerable to digestion by the isoschizomer HpaII only when they are unmethylated, i.e., when they lie on the inactive X chromosome, M27-beta can be used to differentiate between the active and inactive X chromosomes. In the 5 families, they observed 3 manifesting heterozygotes who had presented to a neurologist independently of the illness in affected males in the family. Only 1 of the 3 manifesting carriers showed skewing, but 2 of 9 nonmanifesting carriers did also.
Maestri and Beaty (1992) examined the implications of a 2-locus model to explain heterogeneity in ALD, i.e., the occurrence of severe childhood form (ALD) and the milder adult-onset form (AMN) in the same family, or even the same sibship. They considered 2 models. Under a dominant epistatic model, a single M allele at an autosomal modifier locus ameliorates the most severe effects of the disease allele, thus leading to the milder AMN phenotype; only males with genotype mm would have ALD. Under a recessive epistatic model, 2 copies of the M allele would be necessary to have the milder AMN phenotype. Maestri and Beaty (1992) showed that the recurrence risk for a second affected male depended on the frequency of the protective allele at this modifier locus. They suggested sampling discordant affected sib pairs as a strategy for detecting linkage between a polymorphic DNA marker and a possible modifier gene.
Close linkage of ALD and G6PD was indicated by the absence of recombination in 18 opportunities. This means that the ALD locus is in the terminal segment of the long arm of the X, i.e., Xq28. That the locus is not closely linked to Xg had been shown by Spira et al. (1971). Close linkage to DXS52 (maximum lod score = 4.17 at theta = 0.0) was found by van Oost et al. (1987).
Close linkage of ALD to the cluster of colorblindness genes is indicated by the increased frequency of colorblindness in affected males and by the demonstration of deletion of cone pigment genes with the use of DNA probes (Aubourg et al., 1988). Aubourg et al. (1988) studied the red and green visual pigment genes in 8 kindreds with ALD and demonstrated frequent structural changes, including deletions and intragenic recombinations. Sack et al. (1989) found increased frequency of abnormal color vision in men with adrenomyeloneuropathy and pointed to these findings as supporting very close linkage of the ALD and the colorblindness loci, thus giving the opportunity for contiguous gene defects.Aubourg et al. (1990) reported studies on a large number of patients with ALD. No deletions were found with probes that lie 3-prime of the green pigment genes. One of the 8 previously reported ALD patients had a long deletion 5-prime of the red pigment gene, a deletion causing blue cone monochromacy. This finding and the previous finding of a 45% frequency of phenotypic color vision defects in patients with AMN suggested toAubourg et al. (1990) that the ALD/AMN gene may lie 5-prime to the red pigment gene and that the frequent phenotypic color vision anomalies owe their origin to deleted DNA that includes regulatory genes for color vision. In studies of an ALD patient who also had blue cone monochromacy, Feil et al. (1991) characterized a complex chromosomal rearrangement in band Xq28. Two CpG islands were mapped, at 46 and 115 kb upstream from the visual pigment genes, one or the other of which might mark the location of the ALD gene. Sack et al. (1993) gave a molecular analysis of the chromosomal rearrangement in kindred 'O' reported by Aubourg et al. (1988). Alpern et al. (1993) characterized the physiologic defect in color vision. The DNA in a hemizygous male showed altered restriction fragment sizes compatible with a deletion extending from the 5-prime end of the color pigment gene cluster. The DNA change had removed the red pigment gene and juxtaposed a 15-kb DNA sequence to the remaining pigment gene. Sack et al. (1993) demonstrated linkage with the ALD gene, located centromeric to the color pigment gene cluster; maximum lod = 3.19 at theta = 0.0. On physiologic testing, Alpern et al. (1993) found color matching they interpreted as indicating the presence of an abnormal rudimentary visual pigment. They suggested that this may reflect the presence of a recombinant visual pigment protein or altered regulation of residual pigment genes due to the DNA change: deletion of the long-wave pigment gene and reorganized sequences 5-prime to the pigment gene cluster.
In several large families with ALD, van Oost et al. (1991) extended the linkage of ALD to DXS52 and arrived at a maximal lod score of 22.5 at 1 cM. They also found tight linkage of ALD to F8C and showed that both ALD and F8C are distal to DXS52. No major structural rearrangement in Xqter was observed; in particular, there were no abnormalities in the color vision genes. The occurrence of several cases in which both ALD and Emery-Dreifuss muscular dystrophy (310300) were thought to be present suggested that these loci are closely situated (Moser, 1987); however, the diagnosis of ALD was not confirmed in these patients, and in testing of additional patients with EMD, none was found to have ALD (Moser, 1989). Using probe St14 (DXS52), Boue et al. (1985) and Aubourg et al. (1987) found a total lod score in their combined families of 13.766 at theta = 0. In an analysis of 59 ALD kindreds, Sack and Morrell (1993) found normal hybridization using a probe situated 30 kb centromeric to the color pigment genes. However, using a probe located 100 kb further centromeric, they found 2 overlapping deletions in 2 patients. Additional study indicated that the telomeric ends of the 2 deletions were 8 kb apart. Thus, the location of the ALD gene appeared to have been defined as approximately 150 kb centromeric of the color pigment genes.
Mosser et al. (1993) identified the ALD gene by positional cloning. Sarde et al. (1994) determined that the ALD gene is 720 kb proximal to the R/GCP genes and other genes lie between the two. Thus the occurrence of color vision abnormalities in ALD is not secondary to localization.
Hoefnagel et al. (1962) described the histologic findings in endocrine glands, especially the pituitary and adrenal.
Ropers et al. (1977) described typical morphologic changes in cultured fibroblasts on light microscopy. The changes, seen only 4 or 5 days after subculture, consisted of expansion of the cells, which appeared abnormally large. Lyonization was demonstrated in cultured fibroblasts of the mother.
Ho et al. (1995) predicted that disruptive effects of the accumulation of very long chain saturated fatty acids on cell membrane structure and function may explain the neurologic manifestations of ALD patients. Especially the 26-carbon acid, hexacosanoic acid, is involved. They studied the interaction of radiolabelled hexacosanoic acid with model membranes and bovine serum albumin by NMR spectroscopy to compare properties of the hexacosonoic acid with those of typical dietary fatty acids. Desorption of hexacosanoic acid from membranes was orders of magnitude slower than that of shorter-chain fatty acids and binding to serum albumin was ineffective.
Federico et al. (1988) added to the evidence for autoimmune factors in the pathogenesis of ALD by the description of a 53-year-old man with CNS white matter demyelination and evidence of a multisystem immunologic disorder including autoimmune thyroiditis, antigastric mucosa antibodies, and antismooth muscle antibodies. The cerebrospinal fluid showed a marked increase in IgG index and several oligoclonal bands with an alkaline isoelectric point.
In a review of brain autopsy material from 9 cases of ALD, Eichler et al. (2008) observed marked demyelinative lesions in the white matter with sparing of the subcortical white matter. One additional case of pure adrenomyeloneuropathy did not show white matter demyelination. The lesion edges were regions of active demyelination with macrophages containing granules consisting of lipid inclusions consistent with myelin debris. Dense perivascular aggregates of macrophages and lymphocytes were closer to the lesion, but macrophages were less prominent within the cores of lesions. These findings suggested that macrophages played a phagocytic role but not a role in active myelin destruction. Further studies showed that white matter areas beyond the actively demyelinating edge were essentially devoid of microglia due to apoptosis, whereas microglia density was normal in remote normal brain tissue. Injection of lysophosphatidylcholine in mouse brains induced microglial apoptosis. Eichler et al. (2008) concluded that microglial apoptosis resulting from accumulation of very-long chain fatty acids may be an early change in the pathogenesis of ALD that occurs before demyelination, and that the loss of microglia prevents them from protecting oligodendrocytes and axons.
Hein et al. (2008) found that rat oligodendrocytes and astrocytes exposed to VLCFA in culture died within 24 hours, with the greatest effect on myelin-producing oligodendrocytes. VLCFA caused increased intracellular calcium in oligodendrocytes, astrocytes, and neurons. VLCFA also induced depolarization of mitochondria and promoted permeability of the inner mitochondrial membrane. Hein et al. (2008) concluded that VLCFAs are potently cytotoxic due to mitochondrial dysfunction and calcium deregulation.
Fourcade et al. (2008) found that XLD fibroblasts showed decreased mitochondrial potential and increased sensitivity to oxidative stress. In vitro, the alpha-tocopherol analog Trolox was able to reverse these oxidative defects, as measured by decreased levels of lipoxidative protein damage.
Moser et al. (1981) developed a plasma method for the detection of very long chain fatty acids providing for the diagnosis of affected individuals and assisting in carrier identification. Moser et al. (1999) reported the results of testing with this assay, the most widely used procedure for the diagnosis of X-linked ALD and other peroxisomal disorders, in 3,000 patients and 29,000 controls. VLCFA levels are elevated at birth, and the assay is highly accurate in hemizygotes. Eighty-five percent of obligate heterozygotes will have an elevated level, but a normal result did not exclude carrier status. A variety of other peroxisomal disorders, including Zellweger syndrome and other single enzyme defects in peroxisomal beta oxidation, also share an elevation of VLCFA levels, but can readily be discerned from ALD by the clinical situation.
Moser and Moser (1999) provided an authoritative discussion of the prenatal diagnosis of X-linked ALD. They concluded that measurement of VLCFA levels in cultured amniocytes and chorionic villus cells (the most frequently used procedure) is reliable provided that care is taken to minimize the risk of false-negative results by performance of subcultures in appropriate media. The procedure can be complemented by assays of VLCFA oxidation, and under certain circumstances, immunocytochemical assays for the expression of ALDP. Mutation analysis is the most reliable diagnostic procedure when the nature of the mutation in the at-risk family is known.
Inoue et al. (1996) found abnormal lignoceric acid oxidation in 19 of 19 ALD patients and in 3 of 3 obligate heterozygous carrier women. Among 10 women at risk of being a carrier, 3 with normal levels of VLCFA had abnormal lignoceric acid oxidation. Inoue et al. (1996) suggested that this combined biochemical procedure could improve the accuracy of carrier detection in ALD.
Various techniques have been developed to identify ALD carriers more accurately. Boehm et al. (1999) developed and validated a robust DNA diagnostic test involving nonnested genomic amplification of the ALD gene, followed by fluorescent dye-primer sequencing and analysis.
Lachtermacher et al. (2000) noted that a very small percentage (0.1%) of affected males had plasma C26:0 levels that are borderline normal, and 15% of obligate female carriers have normal results. Effective mutation detection in these families is therefore fundamental to unambiguous determination of genetic status. Of particular concern are female members of kindreds segregating X-ALD mutations, because normal VLCFA levels do not guarantee lack of carrier status. Lachtermacher et al. (2000) described a fast method for detection of X-ALD mutations. The method was based on SSCP analysis of nested PCR fragments followed by sequence-determination reactions. Using this method, they found X-ALD mutations in 30 kindreds, including 15 not previously reported.
Using records from the Kennedy Krieger Institute between 1981 and 1998 and the Mayo Clinic Rochester from 1996 to 1998, Bezman et al. (2001)estimated that the minimum frequency of X-linked ALD hemizygotes in the US is 1:42,000, and that of hemizygotes plus heterozygotes is 1:16,800. Five percent of male probands were estimated to have new mutations. Extended family testing identified asymptomatic hemizygotes, who could benefit from therapy, and heterozygotes, who could benefit from genetic counseling.
Kolodny (1987) concluded that asymptomatic individuals with the adrenomyeloneuropathy gene, as well as patients with this disorder and heterozygotes, may benefit from a combined oleic acid, VLCFA-restricted diet.
Moser (1993) reviewed the film 'Lorenzo's Oil,' a fictionalized account of a family's search for a treatment of ALD, afflicting, in this case, a boy named Lorenzo Odone. Moser (1993) concluded that it overstated the success that can be achieved with the oil, invented conflicts between the parents and the medical establishment, and presented an inaccurate and malicious portrayal of the United Leukodystrophy Foundation. 'Dr. Nicolai,' played in the film by Peter Ustinov, copied Moser's 'appearance and speech with remarkable accuracy.' In an open trial in 14 men with adrenomyeloneuropathy, 5 symptomatic heterozygous women, and 5 boys (mean age, 13 years) with preclinical adrenomyeloneuropathy,Aubourg et al. (1993) could find no evidence of a clinically relevant benefit from dietary treatment with oleic and erucic acids (glyceryl trierucate and trioleate oil; 'Lorenzo's oil'). Asymptomatic thrombocytopenia was noted in 6 patients. Poulos et al. (1994) examined the fatty acid composition of postmortem brain and liver from an adrenoleukodystrophy patient who had received Lorenzo's oil for 9 months. There was improvement in the fatty acid composition of the plasma and liver but not in the brain. This indicated that very little erucic acid crossed the blood-brain barrier. These findings suggested to the authors that dietary supplementation with Lorenzo's oil is of limited value in correcting the accumulation of saturated very long chain fatty acids in the brain of patients with adrenoleukodystrophy.
Treatment with Lorenzo's oil normalizes the level of VLCFA in plasma within 4 weeks. In spite of this promising biochemical effect, clinical results have been disappointing when the oils were fed to symptomatic patients (Aubourg et al., 1993). Moser et al. (1994) reported a positive result in patients in whom therapy was begun before neurologic symptoms were present, suggesting that fatty acid abnormality is of pathogenic significance. However, a 3-year follow-up with somatosensory-evoked potentials and motor-evoked potentials of 8 patients by Restuccia et al. (1999) showed no evidence of any benefit of dietary treatment, even when initiated early in the disease before the appearance of inflammatory lesions.
Moser et al. (2005) identified asymptomatic boys with X-linked adrenoleukodystrophy who had a normal MRI and assessed the effect of Lorenzo's oil (4:1 glyceryl trioleate-glyceryl trierucate) on disease progression. By a plasma very long chain fatty acids assay used to screen at-risk boys, 89 affecteds were identified, and all were treated with Lorenzo's oil and moderate fat restriction. Plasma fatty acids and clinical status were followed for 6.9 +/- 2.7 years. Of the 89 boys, 24% developed MRI abnormalities and 11% developed neurologic and MRI abnormalities. Moser et al. (2005)concluded that reduction of hexacosanoic acid by Lorenzo's oil was associated with reduced risk of developing MRI abnormalities. They recommended therapy with Lorenzo's oil in asymptomatic boys with X-linked adrenoleukodystrophy who had normal brain MRI results. Their experience with other ALD patients and that of Rizzo et al. (1989) indicated that total fat intake in excess of 30 to 35% of total calories may counteract or nullify the C26:0-reducing effect of Lorenzo's oil. Those patients who developed progressive MRI abnormalities should be considered for hematopoietic stem cell transplantation (HSCT) as recommended by Peters et al. (2004). Adrenal function must be monitored since 80% asymptomatic patients with ALD develop evidence of adrenal insufficiency (Dubey et al., 2005) and adrenal hormone replacement therapy should be provided when indicated by laboratory findings. Thus, a 3-prong therapeutic approach is recommended.
Aubourg et al. (1990) achieved reversal of early neurologic and neuroradiologic features in an 8-year-old boy who received bone marrow transplantation (BMT) from his fraternal twin brother. Malm et al. (1997) described experience with bone marrow transplantation in 3 children with ALD. They concluded that BMT must be considered very early, even in a child without symptoms but with signs of demyelination on MRI, if a suitable donor is available.
Shapiro et al. (2000) discussed the experience of BMT in 12 patients over an extended period of time and came to the conclusion that it did result in improved outcome if performed early in the course of symptomatic disease.
Kruse et al. (1994) systematically studied 25 patients with adrenoleukodystrophy. Using multislice proton magnetic resonance spectroscopy, they demonstrated a reduction in N-acetyl aspartate, an increase in choline, and occasionally an increase in lactate. They concluded that magnetic resonance spectroscopic imaging is a more sensitive indicator of early neurologic involvement than is magnetic resonance imaging and therefore a more useful gauge of demyelination by which therapeutic approaches could be judged.
Because of the circumstantial evidence that immunologic factors contribute to the pathogenesis of the CNS lesions in ALD, Naidu et al. (1988)administered cyclophosphamide for 5 to 11 days to 4 patients with childhood ALD and to 1 patient with the adult cerebral form. The rate of neurologic progression in the 4 patients with childhood disease did not differ from that in 167 untreated patients with childhood disease surveyed previously.
Cappa et al. (1994) gave intravenous high-dose immunoglobulins to 6 patients with adrenoleukodystrophy who were already on a restricted very long chain fatty acid diet supplemented with glycerol trioleate/erucic acid. The MRI and symptoms deteriorated in this group at the same rate as they did in 6 control patients on the same restricted/supplemented diet who did not receive immunoglobulins.
El-Deiry et al. (1997) studied the prevalence of adrenal dysfunction in 71 females who were obligate carriers of the X-linked trait by pedigree analysis and whose plasma very long chain fatty acid levels were consistent with a heterozygote status. The authors concluded that, in ALD heterozygotes, adrenal cortical insufficiency rarely develops, although isolated mineralocorticoid insufficiency may occur in these individuals. Furthermore, they inferred that ALD heterozygotes may be predisposed to hypoaldosteronism related to the use of nonsteroidal antiinflammatory agents. A subclinical decrease in glucocorticoid reserve, as measured by synthetic ovine corticotropin releasing hormone testing, may be present in a majority of these women. The authors suggested that aldosterone levels be included in ACTH stimulation testing done to detect adrenal insufficiency in affected women. Nonsteroidal antiinflammatory agents should be considered a risk factor for the development of hypoaldosteronism in women heterozygous for ALD.
Peters et al. (2004) reviewed results in 126 boys with X-ALD who received hematopoietic cell transplantation from 1982 to 1999. Complete data were available and analyzed for 94 boys with cerebral X-ALD. The estimated 5- and 8-year survival was 56%. The leading cause of death was disease progression. Donor-derived engraftment occurred in 86% of patients. Demyelination involved parietal-occipital lobes in 90%, leading to visual and auditory processing deficits in many boys. Peters et al. (2004) concluded that boys with early-stage disease benefit from hematopoietic cell transplantation, whereas boys with advanced disease may be candidates for experimental therapies.
Schonberger et al. (2007) reported a boy with childhood ALD who underwent hematopoietic stem cell transplantation but died from transplant-related complications 76 days later. Postmortem examination showed mixed chimerism of the mutant and wildtype alleles in 23 tissue samples examined, including 12 CNS samples. Normal ALD protein was localized to peroxisomes within multiple cell types, including neurons.Schonberger et al. (2007) noted that detection of ALD protein so soon after transplant may indicate that healthy donor cells assisted affected recipient cells in metabolic function. Peripheral blood samples from an affected male cousin who had successful HSCT showed the wildtype ALD allele exclusively. There was no clinical disease progression after transplant. The findings in both patients indicated that HSCT can result in restoration and widespread presence of intact donor ALD protein in various recipient tissues.
Cartier et al. (2009) initiated a gene therapy trial in 2 ALD patients for whom there were no matched donors for hematopoietic stem cell transplantation. Autologous CD34(+) cells were removed from the patients, genetically corrected ex vivo with a lentiviral vector encoding wildtype ABCD1, and then reinfused into the patients after they had received myeloablative treatment. Over a span of 24 to 30 months of follow-up, Cartier et al. (2009) detected polyclonal reconstitution, with 9 to 14% of granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein.Cartier et al. (2009) concluded that their results strongly suggested that hematopoietic stem cells were transduced in the patients. Beginning from 14 to 16 months after infusion of the genetically corrected cells, progressive cerebral demyelination in the 2 patients stopped, a clinical outcome comparable to that achieved by allogeneic hematopoietic stem cell transplant. Thus, Cartier et al. (2009) concluded that lentiviral-mediated gene therapy of hematopoietic stem cells can provide clinical benefits in ALD.
Engelen et al. (2010) reported the results of a randomized control trial of 40 mg daily lovastatin in 14 patients with ALD. Treatment with lovastatin resulted in a small decrease of plasma C24:0 and C26:0, likely due to a decrease in LDL cholesterol. Levels of C18:1 were also slightly reduced. However, there was no effect on C26:0 in erythrocytes or lymphocytes or on VLCFAs in the LDL lipoprotein fraction. These data indicated lovastatin should not be prescribed as a therapy to lower levels of VLCFAs in patients with ALD. No adverse events were observed.
Fourcade et al. (2010) demonstrated that valproic acid (VPA), a widely used antiepileptic drug with histone deacetylase inhibitor properties, induced the expression of the ABCD2 peroxisomal transporter (601081). VPA corrected the oxidative damage in ALD human fibroblasts and decreased the levels of monounsaturated VLCFA (C26:1 n-9), but not saturated VLCFA. Overexpression of ABCD2 alone prevented oxidative lesions to proteins in a mouse model of ALD. A 6-month pilot trial of VPA in ALD patients resulted in reversion of the oxidative damage to proteins in peripheral blood mononuclear cells.
See the MOLECULAR GENETICS section in 300371.
Moser et al. (1991) reported that their laboratory had identified more than 900 hemizygotes and 1,000 heterozygotes. Approximately 50% of the hemizygotes had a rapidly progressive childhood or adolescent form of the disease. In 25% of males, a slowly progressive paraparesis was the clinical picture. The illness occasionally presented as Addison disease without apparent neurologic involvement. Approximately 15% of heterozygotes developed moderately severe spastic paraparesis.
In studies of 30 Dutch kindreds, van Geel et al. (1994) phenotyped 77 affected males and found that 35 (46%) had adrenomyeloneuropathy and 24 (31%) had the childhood or adolescent cerebral ALD. These percentages differed significantly from previous reports in which 25 to 28% of the patients developed AMN and 53 to 57% developed childhood or adolescent cerebral ALD.
In studies in Australasia and Spain, Kirk et al. (1998) and Ruiz et al. (1998), respectively, provided new information about the epidemiology of ALD and the relative frequency of ALD phenotypes. The first study originated from the unit that had served as the ALD Referral Center in Australasia for the previous 15 years. Based on the number of ALD cases identified during this period and the number of live births, they arrived at a minimum incidence of 1.6 per 100,000 live births, slightly higher than the 1.1 per 100,000 based on similar analyses in the United States (Moser et al., 1995) and considerably higher than the estimated 1 per 200,000 males in the Netherlands (van Geel et al., 1994). Of the 95 affected males studied by Kirk et al. (1998), 51 had cerebral adrenoleukodystrophy, 24 had adrenomyeloneuropathy, 15 had Addison disease only, and 5 remained asymptomatic when last examined. Of the 60 patients belonging to 48 kindreds studied by Ruiz et al. (1998), 33% had childhood cerebral ALD plus adolescent cerebral ALD, 16% had adult cerebral ALD, 27% had adrenomyeloneuropathy, 12% had Addison disease only, and 12% had presymptomatic ALD.
Bezman and Moser (1998) reviewed the relative frequency of phenotypes in 388 patients from 253 sibships from the United States and Canada in whom the genotype and phenotype of every male was known. This determination of every male eliminated the ascertainment bias introduced by other series in which ALD status was not known. When the proband was excluded, the phenotypic breakdown was 33% with childhood cerebral ALD, 26% with adrenomyeloneuropathy, 14% Addison only, 13% asymptomatic, 4% adolescent, and 2% adult cerebral. These numbers were very similar to the series from the Netherlands in which there was an attempt to identify everyone in the country with ALD.
Bezman et al. (2001) determined the minimum frequency of hemizygotes in the United States to be 1:42,000 and that of hemizygotes and heterozygotes to be 1:16,800.
In a retrospective hospital- and clinic-based study involving 122 children with an inherited leukodystrophy, Bonkowsky et al. (2010) found that the most common diagnoses were metachromatic leukodystrophy (250100) (8.2%), Pelizaeus-Merzbacher disease (312080) (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (4.1%). No final diagnosis was reported in 51% of patients. The disorder was severe: epilepsy was found in 49%, mortality was 34%, and the average age at death was 8.2 years. The population incidence of leukodystrophy in general was found to be 1 in 7,663 live births.
Forss-Petter et al. (1997) and Lu et al. (1997) generated mice deficient in ALDP by targeted disruption. Motor functions in Aldp-deficient mice developed on schedule, and unexpectedly, adult animals appeared unaffected by neurologic symptoms up to 6 months of age. Biochemical analyses demonstrated impaired beta-oxidation in mutant fibroblasts and abnormal accumulation of very long chain fatty acids in the CNS and kidney. In 6-month-old mutants, adrenal cortex cells displayed a ballooned morphology and needle-like lipid inclusions, also found in testis and ovaries. However, lipid inclusions and demyelinating lesions of the CNS were not a feature.
Contrary to the original suggestion that there was no phenotype associated with these mice, Pujol et al. (2002) determined that older mice have changes resembling AMN. Older Aldp-deficient mice exhibited an abnormal neurologic and behavioral phenotype, starting at around 15 months. This was correlated with slower nerve conduction and with myelin and axonal anomalies detectable in the spinal cord and sciatic nerve, but not in brain.
The Drosophila recessive mutant 'bubblegum' (bgm) exhibits adult neurodegeneration, with marked dilation of photoreceptor axons. This mutant shows elevated levels of VLCFAs, as seen in ALD. Min and Benzer (1999) found that feeding the fly mutant one of the components of 'Lorenzo's oil,' glyceryl trioleate oil, blocked the accumulation of excess VLCFAs as well as development of the pathology.
In Abcd1-knockout mice, Pujol et al. (2004) demonstrated that axonal damage was the first pathologic event in this model, followed by myelin degeneration. The phenotype could be modulated through expression levels of Abcd2 (601081). Overexpression of Abcd2 in Abcd1-knockout mice prevented both VLCFA accumulation and neurodegenerative features, whereas Abcd1/Abcd2 double mutants exhibited an earlier onset and more severe disease.
Oezen et al. (2005) reported normal VLCFA levels in mitochondria of Abcd1-deficient mice. Polarographic analysis of the respiratory chain as well as enzymatic assays of isolated muscle mitochondria revealed no differences between Abcd1-deficient and control mice. Ultrastructural analysis revealed normal size, structure, and localization of mitochondria in muscle of both groups. Mitochondrial enzyme activity in brain homogenates of Abcd1-deficient and wildtype animals also did not differ, and studies on mitochondrial oxidative phosphorylation in permeabilized human skin fibroblasts of ALD patients and controls revealed no abnormalities. Oezen et al. (2005) concluded that accumulation of VLCFA per se does not cause mitochondrial abnormalities, and vice versa mitochondrial abnormalities are not responsible for the accumulation of VLCFA in Abcd1-deficient mice.
Fourcade et al. (2008) found evidence of lipoxidative protein damage in the spinal cord of Abcd1-null mice as early as 3.5 months of age before the onset of neurologic symptoms. At 12 months, Abcd1-null mice had accumulated additional proteins affected by oxidative damage. Abcd1-null mice, spinal cord slices from these mice, and human ALD fibroblasts all showed a defective antioxidant response to VLCFA.
In early symptomatic Abcd1/Abcd2 double-knockout mice, Mastroeni et al. (2009) demonstrated that intracisternal injection of an adeno-associated viral vector engineered to express human IGF1 (147440) and NTF3 (162660), 2 potent inducers of myelin formation and oligodendrocyte survival, resulted in protective effects against the demyelination process and amelioration of disease progression. Studies of CSF showed persistent expression of the genes after 20 weeks, suggesting effective transduction of leptomeningeal cells and a long-lasting effect.
Moser (1997) suggested that the first patient with X-ALD was described by Haberfeld and Spieler (1910). A previously normal boy developed disturbances in eye movement and vision at the age of 6 years, became apathetic, and showed deterioration of school work. Four months later his gait became spastic, and this progressed to an inability to walk. He was hospitalized at 7 years of age. Dark skin was noted. He died 8 months later. An older brother had died of a similar illness at 8.5 years. The postmortem brain was studied by Schilder (1913) and reported as the second of 3 cases that he referred to as 'encephalitis periaxialis diffusa,' characterized by diffuse involvement of the cerebral hemispheres in children with severe loss of myelin, which resembled multiple sclerosis because of the relative preservation of axons and the accumulation of lymphocytes, fat-laden phagocytes, and glial cells. The findings in the adrenal gland were not reported. Involvement of the adrenal gland was reported bySiemerling and Creutzfeldt (1923).
Blaw (1970) coined the name 'adrenoleukodystrophy.'
Gumbinas et al. (1976) suggested that progressive spastic paraparesis with adrenal insufficiency is 'a distinct disease, differing importantly from adrenoleukodystrophy.'
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