疾患詳細

疾患詳細





#249900
Metachromatic leukodystrophy due to saposin B deficiency
(Metachromatic leukodystrophy due to cerebroside sulfatase activator deficiency)
(Saposin B deficiency)

Saposin B 欠損による異染性白質ジストロフィー
(異染性白質ジストロフィー, cerebroside sulfatase activator欠損症 による)
(サポシン B 欠損症)
指定難病19 ライソゾーム病

責任遺伝子:176801 Prosaposin (PSAP) <10q22.1>
遺伝形式:常染色体劣性

(症状)
(GARD)

 Abnormality of the periventricular white matter (脳室周囲白質異常) [HP:0002518] [160127]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Babinski sign (バビンスキー徴候) [HP:0003487] [0213]
 CNS demyelination (中枢神経脱髄) [HP:0007305] [160127]
 Decreased nerve conduction velocity (神経伝導速度減少) [HP:0000762]
 Developmental regression (発達退行) [HP:0002376] [0125]
 Dysarthria (構音障害) [HP:0001260] [0230]
 Dysphagia (嚥下障害) [HP:0002015] [01820]
 Gait ataxia (歩行失調) [HP:0002066] [028]
 Generalized hypotonia (全身性筋緊張低下) [HP:0001290] [0242]
 Global developmental delay (全般的発達遅滞) [HP:0001263] [0120]
 Hyperreflexia (反射亢進) [HP:0001347] [0241]
 Hyporeflexia (低反射) [HP:0001265] [0242]
 Loss of speech (発語喪失) [HP:0002371] [0233]
 Mental deterioration (知的悪化) [HP:0001268] [0125]
 Muscular hypotonia (筋緊張低下) [HP:0001252] [0242]
 Peripheral demyelination (末梢脱髄) [HP:0011096] [160127]
 Polyneuropathy (ポリニューロパチー) [HP:0001271] [0204]
 Seizures (けいれん) [HP:0001250] [01405]
 Spastic tetraparesis (痙性四肢不全麻痺) [HP:0001285] [0241] [02613]
 Urinary incontinence (遺尿) [HP:0000020] [0192]
 Variable expressivity (多様な表現度) [HP:0003828]

(UR-DBMS)
【一般】12-16 か月までは正常
 発達遅滞, 進行性→進行性歩行喪失
 精神運動退行
 2 または 2.5 歳までに坐できなくなる
 嚥下障害
 けいれん (比較的まれ)
 知能退行
 腹部膨満
 遺尿
【神経】構音障害
 衰弱
 筋緊張低下
 痙縮
 痙性四肢不全麻痺
 反射亢進
 反射低下
 開扇反射
 言語喪失
 失調歩行
 認知低下
 精神病
 ジストニア
 捻転スパスム (頸部, 脊椎, 四肢)
 硬直
 舞踏病アテトーゼ
 ニューロパチー
 筋力低下
 ミオパチー
 末梢性ニューロパチー
 神経伝導速度減少
【眼】眼振
【消化器】巨大結腸
【四肢】反張膝 (下肢病変) → (上肢病変)
【X線】脳室周囲白質異常
 脱髄
【検査】正常または軽度低下した arylsulfatase A 活性
 Saposin B 欠損
 sphingolipids で満たされた粘膜下マクロファージ
【その他】多様な重症度
 多様な発症年齢 (乳児~成人)
 経過は発症年齢による

(要約)
●異染性白質ジストロフィー (MLD, Arylsulfatase A 欠乏症) は, 白質ジストロフィーのファミリーにリストされるリソソーム蓄積症である
 →中枢神経および末梢神経全体の神経繊維の絶縁体として作用する脂肪カバーであるミエリンの成長と発生を障害する
  スルファチドの沈着がある
●原因
 arylsulfatase A 欠乏が直接的原因である
 この酵素がないと体の多くの組織でスルファチドが蓄積する
 →神経の髄鞘を破壊する
●症状
1) 後期乳児型
 最も多い型 (50-60%)で, 通常15-24か月に歩行障害をもつ
 筋萎縮と衰弱, 筋強直, 発達遅滞, 進行性視力障害→盲, けいれん, 嚥下障害, 麻痺, 認知症, 昏睡がみられる
 治療しないと5歳以前に死亡する
2) 若年型 (3–10 歳発症)
 学習障害, 精神悪化, 痴呆症で始まる
 →後期乳児型に類似した症状をもつが, 進行は緩徐である
 死亡年齢は多様であるが, 発症から10-15年以内が多い
3) 成人型
 16歳以後に精神疾患または進行性認知症で発症する
 進行はより緩徐である
●治療
 対症療法
 骨髄移植 (幹細胞移植), 酵素置換療法などが試行

(要約)
●異染性白質ジストロフィー (MLD, Arylsulfatase A 欠乏症) は, 白質ジストロフィーのファミリーにリストされるリソソーム蓄積症である
 →中枢神経および末梢神経全体の神経繊維の絶縁体として作用する脂肪カバーであるミエリンの成長と発生を障害する
  スルファチドの沈着がある
●原因
 arylsulfatase A 欠乏が直接的原因である
 この酵素がないと体の多くの組織でスルファチドが蓄積する
 →神経の髄鞘を破壊する
●症状
1) 後期乳児型
 最も多い型 (50-60%)で, 通常15-24か月に歩行障害をもつ
 筋萎縮と衰弱, 筋強直, 発達遅滞, 進行性視力障害→盲, けいれん, 嚥下障害, 麻痺, 認知症, 昏睡がみられる
 治療しないと5歳以前に死亡する
2) 若年型 (3–10 歳発症)
 学習障害, 精神悪化, 痴呆症で始まる
 →後期乳児型に類似した症状をもつが, 進行は緩徐である
 死亡年齢は多様であるが, 発症から10-15年以内が多い
3) 成人型
 16歳以後に精神疾患または進行性認知症で発症する
 進行はより緩徐である
●治療
 対症療法
 骨髄移植 (幹細胞移植), 酵素置換療法などが試行

(Responsible gene) *176801 Prosaposin (PSAP) <10q22.1>
(1) Metachromatic leukodystrophy due to saposin B deficiency (249900)
.0001 Metachromatic leukodystrophy due to saposin B deficiency [PSAP, THR217ILE [dbSNP:rs121918103] (RCV000014289...) (Kretz et al. 1989, 1990; Wenger et al. 1989; Rafi et al. 1990)
Note: The codon number 23 refers to the twenty-third residue of mature saposin B. The codon number 217 (previously listed here as 216) refers to that of the immature prosaposin polypeptide.
.0002 Metachromatic leukodystrophy due to saposin B deficiency [PSAP, IVS4AS, C-A] (RCV000014290) (Wenger et al. 1989; Zhang et al. 1990)
.0003 Metachromatic leukodystrophy due to saposin B deficiency [PSAP, CYS241SER] (dbSNP:rs121918104) (RCV000014291...) (Holtschmidt et al. 1991)
.0006 Metachromatic leukodystrophy due to saposin B deficiency [PSAP, IVS5AS, G-T, -1] (RCV000014295) (Henseler et al. 1996)
.0007 Metachromatic leukodystrophy due to saposin B deficiency [PSAP, ASN215HIS] (dbSNP:rs121918107) (RCV000014296) (Wrobe et al. 2000; Remmel et al. 2007)
.0014 Metachromatic leukodystrophy due to saposin B deficiency [PSAP, IVS5AS, A-G, -2] (RCV000014303) (Kuchar et al. 2009)
.0015 Metachromatic leukodystrophy due to saposin B deficiency [PSAP, 2-BP DEL, 828GA] (RCV000014304) (Kuchar et al. 2009)
(2) Gaucher disease, atypical, due to saposin C deficiency (610539)
.0004 Gaucher disease, atypical, due to saposin C deficiency [PSAP, CYS385PHE [dbSNP:rs121918105] (RCV000014292) (Schnabel et al. 1991)
.0010 Gaucher disease, atypical, due to saposin C deficiency [PSAP, CYS382GLY] (dbSNP:rs121918108) (RCV000014299) (Rafi et al. 1993)
.0011 Gaucher disease, atypical, due to saposin C deficiency [PSAP, GLN430TER] (dbSNP:rs121918109) (RCV000014300) (Diaz-Font et al. 2005)
.0012 Gaucher disease, atypical, due to saposin C deficiency [PSAP, LEU349PRO] (dbSNP:rs121918110) (RCV000014301) (Tylki-Szymanska et al. 2007)
(3) Combined saposin deficiency (611721)
.0005 Combined saposin deficiency (Gaucher disease, atypical, due to saposin C deficiency, included) [PSAP, MET1LEU [dbSNP:rs121918106] (RCV000014293...) (Harzer et al. 1989; Schnabel et al. 1992; Bradova et al. 1993; Tylki-Szymanska et al. 2007)
.0008 Combined saposin deficiency [PSAP, 1-BP DEL, 803G] (RCV000014297) (Hulkova et al. 2001)
.0013 Combined saposin deficiency [PSAP, IVS9AS, A-G, -2] (RCV000014302) (Kuchar et al. 2009)
(4) Krabbe disease, atypical, due to saposin A deficiency (611722)
.0009 Krabbe disease, atypical, due to saposin A deficiency (611722) [PSAP, 3-BP DEL, 207TGT] (RCV000014298) (Spiegel et al. 2005)

(Note)
A number sign (#) is used with this entry because of evidence that metachromatic leukodystrophy due to saposin B deficiency is caused by homozygous or compound heterozygous mutation in the prosaposin gene (PSAP; 176801) on chromosome 10q22.

This disorder is genetically distinct from metachromatic leukodystrophy (MLD; 250100) due to deficiency of arylsulfatase A (ARSA; 607574).

Clinical Features
Shapiro et al. (1979) and Hahn et al. (1982) described 3 patients from 2 families with metachromatic leukodystrophy and normal arylsulfatase A activity.

Stevens et al. (1981) defined this biochemically distinct form of metachromatic leukodystrophy in 2 sibs of consanguineous Mexican-American parents. The clinical picture was that of juvenile MLD. Instead of the expected profound deficiency of arylsulfatase A, their enzyme levels were about half-normal, and the enzyme from fibroblasts had properties identical to those of normal fibroblasts. Nevertheless, hydrolysis of cerebroside sulfate by growing fibroblasts was markedly attenuated. Supplementation of the fibroblasts with the cerebroside sulfatase activator saposin B normalized the response in the loading test. The cerebroside sulfatase activator was purified and characterized as a heat stable, low molecular weight, anionic, lysosomal protein that exerts its effects by interacting with and dispersing the hydrophobic sulfatide (Fischer and Jatzkewitz, 1977). A bile salt such as sodium taurodeoxycholate or sodium cholate could substitute for the activator, indicating its essentially detergent mechanism of action. With a monoclonal antibody, Inui et al. (1983) demonstrated little or no CRM for the activator protein. They also demonstrated that sulfatide metabolism in cultured cells from the patient of Shapiro et al. (1979)could be corrected not only by the sulfatide sulfatase activator protein but also by the activator protein for GM1 ganglioside beta-galactosidase, indicating possible identity of these proteins.

Wenger et al. (1989) described a fourth case of saposin B deficiency. The infant, who was unusually severely affected, was born of Nigerian parents.

Rafi et al. (1992) demonstrated that cultured cells deficient in SAPB had correction of sulfatide metabolism when transfected with a virally transferred prosaposin cDNA; the cells produced normal levels of mature SAPB.

Henseler et al. (1996) reported a Turkish boy, born of consanguineous parents, with juvenile metachromatic leukodystrophy. He acquired the ability to walk autonomously at age 14 months, but later developed motor difficulties and ceased walking at age 24 months. Clinical examination at age 25 months showed signs of peripheral neuropathy and slight psychologic delay. Laboratory studies showed normal arylsulfatase A activity with increased urinary excretion of sulfatides and globotriaosylceramide. Cultured fibroblasts of the patient metabolized very little endocytosed-labeled sulfatide in a sulfatide-loading experiment; normal catabolism was restored when mature saposin B was added to the culture medium.

Wrobe et al. (2000) reported a 4-year-old girl of Spanish ancestry with saposin B deficiency. At the age of 2 years, she showed severe motor deterioration, hypotonia, weakness, and signs of CNS demyelination and polyneuropathy. At 4 years of age, nerve conduction was severely decreased, and sural nerve biopsy showed active demyelination and metachromatic deposits in macrophages. A bone marrow transplant (BMT) was attempted at the age of 4 years 9 months, but the child died 2 months postengraftment. Her younger sister, aged 2 years, also showed moderate hypotonia, patellar hyperreflexia, and signs of initial occipital demyelination, and BMT was performed at the age of 2 years 8 months.

Kuchar et al. (2009) reported a boy with saposin B deficiency. He presented at age 9 months with signs of a mild, right-sided spastic hemiparesis. By age 2 years, he lost the previously acquired ability to walk a few steps, and showed decreased muscle strength with hyporeflexia. At age 43 months, he developed seizures, lost speech, and had spastic tetraparesis with almost no use of his hands. There was a progressive deterioration, and he was severely disabled at age 6 years with unreactive pupils. Brain MRI showed extensive white matter lesions and evidence of an old infarction. Urine analysis showed increased levels of sulfatide, similar to those seen in metachromatic leukodystrophy. Genetic analysis identified compound heterozygosity for 2 mutations in the PSAP gene (176801.0014 and 176801.0015), resulting in complete loss of 1 allele and generation of transcripts with deletions affecting only the SapB domain from the other allele.

Clinical Management
Landrieu et al. (1998) performed allogenic bone marrow transplantation in a 2-year-old boy with metachromatic leukodystrophy due to saposin B deficiency, and with involvement mainly of the peripheral nervous system. Transient deterioration was observed, followed by continuous improvement of peripheral nervous system functions. These findings were supported by nerve conduction velocity measurements, but the symptoms ultimately worsened. Magnetic resonance imaging showed persistent white matter lesions and progressive pontocerebellar atrophy.

Molecular Genetics
In a Turkish boy with metachromatic leukodystrophy due to saposin B deficiency, Henseler et al. (1996) identified a homozygous mutation in the PSAP gene (176801.0006).

In a 4-year-old girl of Spanish ancestry with saposin B deficiency, Wrobe et al. (2000) identified a mutation in the PSAP gene (176801.0007).

(文献)
(1) Fischer G, Jatzkewitz H. The activator of cerebroside sulphatase: binding studies with enzyme and substrate demonstrating the detergent function of the activator protein. Biochim Biophys Acta 481: 561-572, 1977
(2) Shapiro LJ et al. Metachromatic leukodystrophy without arylsulfatase A deficiency. Pediat Res 13: 1179-1181, 1979
(3) Stevens RL et al. Cerebroside sulfatase activator deficiency induced metachromatic leukodystrophy. Am J Hum Genet 33: 900-906, 1981
(4) Hahn AF et al. A variant form of metachromatic leukodystrophy without arylsulfatase deficiency. Ann Neurol 12: 33-36, 1982
(5) Inui K et al. Immunological evidence for deficiency in an activator protein for sulfatide sulfatase in a variant form of metachromatic leukodystrophy. Proc Nat Acad Sci 80: 3074-3077, 1983
(6) Inui K, Wenger DA: Concentrations of an activator protein for sphingolipid hydrolysis in liver and brain samples from patients with lysosomal storage diseases. J Clin Invest 72: 1622-1628, 1983
(7) Kihara H et al. Genetic complementation in somatic cell hybrids of cerebroside sulfatase activator deficiency and metachromatic leukodystrophy fibroblasts. Hum Genet 66: 300-301, 1984
(8) Wenger DA, Inui K: Studies on the sphingolipid activator protein for the enzymatic hydrolysis of GM1 ganglioside and sulfatide. In Brady RO, Barranger JA (eds.): The Molecular Basis of Lysosomal Storage Disorders. New York: Academic Press, Pp. 61-78, 1984
(9) Wenger DA et al. Clinical, pathological, and biochemical studies on an infantile case of sulfatide/GM1 activator protein deficiency. Am J Med Genet 33: 255-265, 1989
(10) Rafi MA et al. Correction of sulfatide metabolism after transfer of prosaposin cDNA to cultured cells from a patient with SAP-1 deficiency. Am J Hum Genet 50: 1252-1258, 1992
(11) Henseler M et al. Analysis of a splice-site mutation in the sap-precursor gene of a patient with metachromatic leukodystrophy. Am J Hum Genet 58 (1): 65-74, 1996
(12) Landrieu P et al. Bone marrow transplantation in metachromatic leukodystrophy caused by saposin-B deficiency: a case report with a 3-year follow-up period. J. Pediat. 133: 129-132, 1998
(13) Wrobe, D.; Henseler, M.; Huettler, S.; Pascual Pascual, S. I.; Chabas, A.; Sandhoff, K. : A non-glycosylated and functionally deficient mutant (N215H) of the sphingolipid activator protein B (SAP-B) in a novel case of metachromatic leukodystrophy (MLD). J. Inherit. Metab. Dis. 23: 63-76, 2000
(14) Kuchar, L., Ledvinova, J., Hrebicek, M., Myskova, H., Dvorakova, L., Berna, L., Chrastina, P., Asfaw, B., Elleder, M., Petermoller, M., Mayrhofer, H., Staudt, M., Krageloh-Mann, I., Paton, B. C., Harzer, K. Prosaposin deficiency and saposin B deficiency (activator-deficient metachromatic leukodystrophy): report on two patients detected by analysis of urinary sphingolipids and carrying novel PSAP gene mutations. Am. J. Med. Genet. vol. 149A, 613-621, 2009

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