疾患詳細

疾患詳細



歯肉の毛細血管拡張性病変 (Gorlin et al. 1990 より引用)

#230000
Fucosidosis
(Alpha-L-fucosidase deficiency)

フコシドーシス
(α-L-フコシダーゼ欠損症)
指定難病19 ライソゾーム病
小児慢性特定疾病 代81 フコシドーシス

責任遺伝子:612280 Fucosidase, alpha-1 (FUCA1) <1p34>
遺伝形式:常染色体劣性

(症状)
(GARD)
 <80%-99%>
 Anterior beaking of lumbar vertebrae (前方くちばし状腰椎) [HP:0008430] [161505]
 Brachycephaly (短頭) [HP:0000248] [03004]
 Coarse facial features (粗な顔貌) [HP:0000280] [0408]
 Dysostosis multiplex (多発性異骨症) [HP:0000943] [-]
 Failure to thrive (成長障害) [HP:0001508] [01411]
 Generalized hyperkeratosis (全身性過角化症) [HP:0005595] [18019]
 Global developmental delay (全般的発達遅滞) [HP:0001263] [0120]
 Hearing impairment (難聴) [HP:0000365] [091]
 Hepatomegaly (肝腫) [HP:0002240] [01813]
 Hyperhidrosis (多汗) [HP:0000975] [18016]
 Hypothyroidism (甲状腺機能低下症) [HP:0000821] [2121]
 Intellectual disability, severe (重度知的障害) [HP:0010864] [0120]
 Kyphosis (後弯) [HP:0002808] [161500]
 Lipoatrophy (脂肪萎縮症) [HP:0100578] [18045]
 Mucopolysacchariduria (ムコ多糖症) [HP:0008155] [2066]
 Prominent forehead (目立つ額) [HP:0011220] [0501]
 
 <30%-79%>
 Abnormality of the gallbladder (胆嚢異常) [HP:0005264] [1212]
 Corneal opacity (角膜混濁) [HP:0007957] [0620]
 Decreased muscle mass (筋量減少) [HP:0003199] [0270]
 Muscular hypotonia (筋緊張低下) [HP:0001252] [0242]
 Seizures (けいれん) [HP:0001250] [01405]
 Spastic tetraplegia (痙性四肢麻痺) [HP:0002510] [02613]
 Vascular skin abnormality (皮膚血管異常) [HP:0011276] [-]
 
 <5%-29%>
 Abnormal pyramidal sign (錐体路サイン異常) [HP:0007256] [02140][01405][0213]
 Abnormality of the dentition (歯異常) [HP:0000164] [083]
 Abnormality of the nail (爪異常) [HP:0001597] [19]
 Acrocyanosis (肢端チアノーゼ) [HP:0001063] [01406]
 Cardiomegaly (心拡大) [HP:0001640] [1121]
 
 
 Abnormality of the abdominal wall (腹壁異常) [HP:0004298] [1200]
 Absent/hypoplastic coccyx (尾骨欠損/低形成) [HP:0008436] [1147]
 Absent/hypoplastic paranasal sinuses (副鼻腔欠損/低形成) [HP:0005453] [0525]
 Angiokeratoma (被角血管腫) [HP:0001014] [2302]
 Anhidrosis (無汗) [HP:0000970] [18013]
 Anterior beaking of thoracic vertebrae (胸椎の前方楔) [HP:0004630] [161505]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Barrel-shaped chest (樽状胸) [HP:0001552] [11004]
 Cerebral atrophy (大脳萎縮) [HP:0002059] [160121]
 Cervical platyspondyly (扁平頚椎) [HP:0004558] [161505]
 Coxa valga (外反股) [HP:0002673] [15110]
 Dry skin (乾いた皮膚) [HP:0000958] [18039]
 Elevated sweat chloride (汗中クロール増加) [HP:0012236] [2041]
 Flexion contracture (屈曲拘縮) [HP:0001371] [15100]
 Frontal bossing (前頭突出) [HP:0002007] [0501]
 Hernia (ヘルニア) [HP:0100790] [120]
 Hypersplenism (脾臓機能亢進) [HP:0001971] [1213]
 Intellectual disability (知的障害) [HP:0001249] [0120]
 Lumbar hyperlordosis (腰椎前弯) [HP:0002938] [161501]
 Macroglossia (巨舌) [HP:0000158] [08109]
 Oligosacchariduria (オリゴ糖尿症) [HP:0010471] [2064]
 Polyneuropathy (ポリニューロパチー) [HP:0001271] [0204]
 Recurrent respiratory infections (反復性呼吸器感染) [HP:0002205] [014230]
 Scoliosis (側弯) [HP:0002650] [161502]
 Shield chest (盾状胸) [HP:0000914] [11009]
 Short stature (低身長) [HP:0004322] [0130]
 Splenomegaly (脾腫) [HP:0001744] [01817]
 Thick eyebrow (眉毛叢生) [HP:0000574] [1721]
 Thick lower lip vermilion (厚い下口唇唇紅部) [HP:0000179] [05522]
 Tortuosity of conjunctival vessels (結膜血管蛇行) [HP:0000503] [0652]
 Vacuolated lymphocytes (空胞性リンパ球) [HP:0001922] [2212]
 Wide nose (幅広い鼻) [HP:0000445] [0703]

(UR-DBMS)
フコシドーシス
 alpha-L-fucosidase 活性なし (白血球, 線維芽細胞)
 フコース含有オリゴ糖とsphingolipid の増加 (尿または組織)
< I 型 >
【一般】(けいれん)
【神経】生後第1年から進行 → *進行性大脳変性
 筋緊張低下 / 衰弱 → 痙性四肢麻痺
【頭】短頭
【顔】前額突出
【眼】かすかな角膜混濁
 両眼開離
【鼻】幅広い鼻
【心】心筋症
 心拡大
【胃腸管】進行性胆嚢機能障害
【X線】後弯
 くちばし状脊椎骨
【皮膚】多汗
 分厚い皮膚
【毛髪】眉毛叢生
【検査】汗中Na / Cl 増加 (正常の3-9倍)
【血液学】リンパ球空胞化
< II 型>
【一般】*精神遅滞
 低身長
 脱水
 反復性呼吸器感染症
 肝腫
 脾腫
【神経】末梢神経ニューロパチー
 痙縮
 筋成長障害
【頭】巨脳
【顔】粗い顔貌
 分厚い口唇
 副鼻腔欠損/低形成
【眼】牛眼網膜症
 網膜血管異常
 結膜血管蛇行
 両眼開離
【口】歯肉と口唇の毛細血管拡張性病変
 巨舌
【胸郭】心筋炎
 幅広い胸
 幅広い鎖骨
 ヘラ状肋骨
【体幹】ヘルニア
【骨盤】幅広い彫刻された寛骨臼蓋
 外反股
【四肢】関節拘縮
【X線】先細りの中手骨
 MPS III 類似の骨格異常
 進行性板間層肥厚
 腰部前弯
 短い歯状突起
 頸椎扁平
 胸腰部脊椎骨の前方くちばし
 側弯
 小さな第5腰椎骨
 尾骨欠損/低形成
 大脳萎縮
【皮膚】丘疹
 減汗症
 体重減少
 薄く乾いた皮膚
【毛髪】眉毛叢生
【検査】ムコ多糖尿
【腫瘍】*角化血管腫 (3歳近辺で)
【その他】大多数の患者はイタリアと米国南西部
 2つの型がある:乳児型 (type I)と軽症型 (type II)

(要約)
●フコシドーシス (alpha-l-fucosidase 欠乏症)は, まれな常染色体劣性リソソーム蓄積症で, fucosidase がフコースを適切に分解できない
 欠損では, 糖鎖が蓄積し, 最終的にフコシドーシスの臨床症状を生じる
 症状は時間とともに重症度が進行するかもしれない
 フコシドーシスは9つの証明された糖タンパク蓄積症の1つである
●alpha-fucosidase (FUCA1)は, 1p34にマップされる
●型:発症年齢と症状により I 型と II 型に分けられる
1)I 型
 生後3-18か月でみられる
 顔貌異常, 肝脾腫, +/-心拡大, 骨変形がみられる
 チェリーレッド斑がみられうる
 精神遅滞とけいれんもみられる
 血管病変はないが, 急速な精神運動退行, 重度で急速な進行性神経症状, 汗中のNaとCl歯胃切増加, 6歳以前の死亡がみられる
1)II 型
 角化血管腫, 軽度の精神運動発達遅滞と神経症状, 長い生存期間, 汗電解質正常がみられる
 12-24か月令でみられることが多い
 軽度の顔貌異常, 骨変形, 精神遅滞および肝脾

<小児慢性特定疾病 代81 フコシドーシス>
概要・定義
フコシドーシスはライソゾーム酵素であるα-L-フコシダーゼ(EC3.2.1.51)の遺伝的欠損により, フコースを含む各種の糖蛋白質, 糖脂質が全身の細胞のライソゾーム内に蓄積し, 進行性の精神運動発達遅滞をきたす常染色体劣性遺伝疾患である。ライソゾーム病の中でも特に頻度が低く, 患者は全世界に分布しているが百数十例の報告にすぎない。臨床的に2種類の型に分けられることが多い。乳幼児期に精神運動発達遅滞で発症し進行が早く, 汗のNaCl濃度の上昇を特徴とする重症型であるI型と, 1-2歳で発症し進行が遅く被角血管腫(angiokeratoma corporis diffusum)を特徴とする軽症のII型である。
症状
臨床的に精神運動発達遅滞, 神経学的退行, 粗な顔貌, 低身長, 易感染性などを高率に認められ, 約半数で脊柱後側彎, 多発性骨形成不全, 被角血管腫, 関節拘縮, けいれんと肝脾腫が認められる。また難聴, ヘルニア, 視力障害なども認めることがある。
診断方法
臨床所見, 生化学分析, および遺伝子解析に基づいて行う。
1. 臨床症状;臨床的に精神運動発達遅滞, 神経学的退行, 粗な顔貌, 低身長, 易感染性などを高率に認められ, 約半数で脊柱後側彎, 多発性骨形成不全, 被角血管腫, 関節拘縮, けいれんと肝脾腫が認められる。また難聴, ヘルニア, 視力障害なども認めることがある。
2. 臨床検査;MRIでのT2強調画像で淡蒼球が低信号, リンパ球の空胞形成, 尿中に多量のフコースを含む糖蛋白質, オリゴ糖が排泄されているが尿中ムコ多糖の排泄増加のない, ことなどが検査で重要である
3. 確定診断;末梢血白血球, 培養皮膚線維芽細胞のα-L-フコシダーゼ活性の著明な低下を証明する, α-L-フコシダーゼの遺伝子検査
当該事業における対象基準
全A  疾患名に該当する場合
診断
MRIでのT2強調画像で淡蒼球が低信号, リンパ球の空胞形成, 尿中に多量のフコースを含む糖蛋白質, オリゴ糖が排泄されているが尿中ムコ多糖の排泄増加のない, ことなどが検査で重要である。確定診断は末梢血白血球, 培養皮膚線維芽細胞のα-L-フコシダーゼ活性の著明な低下を証明する。もしくはα-L-フコシダーゼの遺伝子検査がある。
治療
神経症状に対する支持療法などが主たる治療法である。造血幹細胞移植の報告がある。
成人期以降
特に軽症型は進行も緩徐であり, 成人期に至ることも多いと考えられる。側弯症に対する治療, 易感染性に対する対応などが重要であり, 進行したあとは経管栄養, 気管切開, 人工呼吸器の適応について検討を要する。被角血管腫からの出血, 鼻ポリープの対応を要することがある。

(Occurrence) 50 cases
(c.f.) FUCA1P (pseudogene) 2q31-q32
(Responsible gene) *612280 Fucosidase, alpha-1 (FUCA1) <1p34>
.0001 Fucosidosis (230000) [FUCA1, GLN351TER] (dbSNP:rs118204450) (RCV000000716) Kretz et al. 1989)
.0002 Fucosidosis [FUCA1, 2EX, DEL] (RCV000000717) (Willems et al. 1991)
.0003 Fucosidosis [FUCA1, GLU375TER] (dbSNP:rs80358195) (RCV000000718) (Yang et al. 1992)
.0004 Fucosidosis [FUCA1, IVS5DS, G-A, +1] (RCV000000719) (Williamson et al. 1993)
.0005 Fucosidosis [FUCA1, GLN77TER] (dbSNP:rs80358196) (RCV000000720) (Seo et al. 1993)
.0006 Fucosidosis [FUCA1, TRP382TER] (dbSNP:rs80358197) (RCV000000721) (Seo et al. 1993)
.0007 Fucosidosis [FUCA1, TYR211TER] (dbSNP:rs80358198) (RCV000000722) (Seo et al. 1993)
.0008 Fucosidosis [FUCA1, 1-BP DEL, PRO141FS] (RCV000000723) (Seo et al. 1993)
.0009 Fucosidosis [FUCA1, 1-BP DEL, SER265FS] (RCV000000724) (Seo et al. 1993)
.0010 Fucosidosis [FUCA1, SER216FS] (RCV000000725) (Seo et al. 1993)
.0011 FU1/FU2 polymorphism [FUCA1, GLN281ARG] (dbSNP:rs13551) (ExAC:rs13551) (RCV000382814...) (Cragg et al. 1994)
.0012 Fucosidosis[FUCA1, LEU405ARG] (dbSNP:rs80358199) (RCV000000727) (Fleming et al. 1998)

(Note)
A number sign (#) is used with this entry because of evidence that fucosidosis is caused by homozygous or compound heterozygous mutation in the FUCA1 gene (612280) on chromosome 1p36.

Fucosidosis is an autosomal recessive lysosomal storage disease caused by defective alpha-L-fucosidase with accumulation of fucose in the tissues. Clinical features include angiokeratoma, progressive psychomotor retardation, neurologic signs, coarse facial features, and dysostosis multiplex.

Fucosidosis has been classified into 2 major types. Type 1 is characterized by rapid psychomotor regression and severe neurologic deterioration beginning at about 6 months of age, elevated sweat sodium chloride, and death within the first decade of life. Type 2 is characterized by milder psychomotor retardation and neurologic signs, the development of angiokeratoma corporis diffusum, normal sweat salinity, and longer survival (Kousseff et al., 1976).

Clinical Features
Van Hoof and Hers (1968) found deficiency of alpha-fucosidase activity in the liver of patients with a Hurler-like disorder described by Durand et al. (1967, 1968). Fucose accumulated in all tissues (Durand et al., 1969). Durand et al. (1968) called the condition fucosidosis. The Belgian patient studied by Loeb et al. (1969) was probably related to the 2 Italian patients reported by Durand et al. (1969).Durand et al. (1969) described type 1 fucosidosis and Loeb et al. (1969) described type 2.

Schafer et al. (1971) found deficiency of alpha-L-fucosidase in a 9-year-old child with an unusual spondylometaphyseoepiphyseal dysplasia.

Patel et al. (1972) described a different phenotype resulting from deficiency of alpha-L-fucosidase. The patient, who was not Hurler-like in appearance, showed unusual survival (to at least 20 years) and from age 4 had angiokeratoma of the skin as in Fabry disease (301500). Differing from Fabry disease were severe mental and physical retardation and normal renal function. He also showed anhidrosis and inability to control body temperature. Urinary and leukocyte alpha-L-fucosidase was 10% of normal; obligate heterozygotes had intermediate values. This is, presumably, an example of allelism with production of quite a different clinical picture.

Schoonderwaldt et al. (1980) discussed a possible third type of fucosidosis based on age of onset and length of survival. They described type 3 as a juvenile form of the disease, with less rapid psychomotor and neurologic deterioration than in types 1 and 2, with survival into the twenties in some cases, and in all cases the typical rash of Fabry disease (angiokeratomata). They described 2 Dutch brothers with some characteristics of type 2, but more like type 3 from the point of view of rate of progression and length of survival; however, the brothers did not show angiokeratoma. The skin was distinctively dry and thin, a feature not described in other patients.

Ikeda et al. (1984) studied 3 sisters with the adult form of fucosidosis (type 2 in the classification of Kousseff et al., 1976). They had prominent psychomotor retardation, gargoyle features, and angiokeratoma. Abnormalities were found in macrophages, endothelial cells, fibroblasts, and Schwann cells on rectal biopsy.

Willems et al. (1988) described 2 families, 1 with 3 patients and the other with 2 patients, in each of which both type 1 and type 2 fucosidosis were represented. In 1 family described by Willems et al. (1988), 1 patient survived to almost 20 years of age and showed angiokeratoma, whereas 2 other patients in a cousin sibship died under age 5 years. All 4 parents were traced to common ancestors; thus, the children were presumably homozygous for the same gene defect. In the second family, 1 patient was alive at almost 25 years of age, whereas a sib had died at age 4 years. Both had angiokeratoma.Willems et al. (1988) suggested that environmental factors or 'modifying genes' separate from the fucosidase structural gene may contribute to the phenotype.

Willems et al. (1991) reviewed the literature on 77 patients with fucosidosis. They presented 4 lines of evidence suggesting that the distinction between a severe type 1 form and a less severe type 2 form with survival into adulthood may not reflect true genetic heterogeneity. First, family pedigrees have shown both types within a single family. Second, clinical studies failed to show a clear distinction between types 1 and 2, but rather a seemingly continuous clinical spectrum. Third, no biochemical heterogeneity has been observed. Very low to negligible residual fucosidase enzyme activity has been found in patients of both types. Fourth, the identical DNA mutation has been found in the homozygous state in patients with the rapidly or slowly progressive form of the disease. The authors speculated that types 1 and 2 fucosidosis, rather than representing 2 distinct clinical entities, represent the extremes of a continuous clinical spectrum.

Fleming et al. (1998) described a leu405-to-arg mutation in the FUCA1 gene (612280.0012) in homozygous state in a patient who was 46 years old the time of review in 1997. There was said to be the first report of a patient with fucosidosis living into the fifth decade. The patient had been described by Primrose (1975) at the age of 20 years with progressive physical and mental retardation, short stature, angiokeratoma corporis diffusum, dysostosis multiplex, and generalized muscle wasting. Her parents were consanguineous. By age 46 years she had lost all verbal and most nonverbal communication and was nonambulant and unable to sit unaided. She had suffered continued muscle wasting, several minor long-bone fractures, and 1 chest infection. She had been noted to be unhappy at warm temperatures and had seldom, if ever, been observed to perspire. Her height was 113 cm. Prominent angiokeratomas were present on the thighs, legs, and trunk, and there was a network of fine capillaries on the limbs. There had been little progression of the angiokeratomas from age 20 to 46 years. The authors noted that hypohidrosis and poor temperature regulation is a recognized feature in this disorder.

Biochemical Features
Patients with fucosidosis have difficulty in degrading fucose-containing blood group H and Lewis substances. In 2 affected sibs in a family of Italian extraction, Kousseff et al. (1976) found that Lewis A and B antigens were very high in both red cells and saliva. However, H specificity showed no increase. Because Lewis-specific alpha-fucose is bound to beta-N-acetyl-D-glucosamine by an alpha-1 to -4 linkage, whereas H-specific alpha-fucose is linked to beta-galactose by an alpha-1 to -2 linkage, the fucosidase that is deficient in fucosidosis may be the one for the 1-to-4 linkage, or, alternatively, the mutation may be such that only that specificity is lost. The last possibility is based on the notion that different mutations of the same enzyme molecule are responsible for the 2 types of fucosidosis (and perhaps for the skeletal dysplasia described by Schafer et al., 1971). This idea follows from the one-gene/one-enzyme/many-substrates idea of O'Brien (1975) and the notion that mutation can interfere with one or another but not all substrate specificities.

Gatti et al. (1973) emphasized heterogeneity in fucosidosis. Johnson and Dawson (1985) presented molecular evidence for heterogeneity among patients with fucosidosis. They studied 11 patients with less than 5% of normal alpha-L-fucosidase activity: in 8 patients, fibroblasts synthesized no detectable enzyme protein; in 2, they synthesized normal amounts of the 53,000-Da precursor, but none of the mature 50,000-Da form was detectable; and in 1, they contained small amounts of crossreacting material.

Population Genetics
A majority of earlier-reported cases of fucosidosis were Italian; most of these patients originated from 2 neighboring villages, Grotteria and Mammola, in the southern Italian province of Reggio Calabria (Sangiorgi et al., 1982).

Willems et al. (1999) stated that fewer than 100 patients with fucosidosis had been reported worldwide. The disease occurred at a higher rate in Italy, in the Hispanic-American population of New Mexico and Colorado, and in Cuba.

Molecular Genetics
Darby et al. (1988) found 2 RFLPs in the FUCA gene in Caucasians; the polymorphism information content (PIC) of the combined DNA markers was 0.38. No recombinants were observed between fucosidosis phenotype and these RFLP markers, suggesting that the lesion responsible for fucosidosis is located in the FUCA1 gene.

In the course of Southern blot analysis of the FUCA1 gene in 23 patients with fucosidosis, Willems et al. (1988) found in 5 patients obliteration of an EcoRI restriction site in the open reading frame encoding mature alpha-L-fucosidase. This abnormality was not observed in 80 controls and was thought to be the basic defect responsible for fucosidosis in these patients. Both patients with the severe type 1 form and patients with the less severe type 2 were shown to be homozygous for this presumed mutation. In the remaining 18 patients, no EcoRI site obliteration, major gene deletions, or insertions were detected. The heterogeneity found at the DNA level was not present at the protein level, as all fucosidosis patients investigated had low fucosidase protein (less than 6% of normal) and negligible fucosidase activity in fibroblasts and lymphoblastoid cell lines.

In 6 unrelated Italian patients with fucosidosis, Guazzi et al. (1989) found 3 patterns of mRNA. One patient showed a variant pattern of DNA hybridization with a partial length cDNA; the change represented loss of an EcoRI site. The same patient showed a markedly decreased amount of mRNA on Northern blot hybridization. Two patients apparently lacked mRNA. The other 3 patients showed a transcript similar in size and amount to that observed in controls.

Kretz et al. (1989) demonstrated that the loss of the EcoRI site identified by Willems et al. (1988) and Guazzi et al. (1989) is determined by a C-to-T transition in the FUCA1 gene, which results in the generation of an in-frame TAA stop codon 120-bp upstream of the normal stop codon (612280.0001).

Gordon et al. (1995) described dystonia of lower extremities in an affected 7-year-old boy. There was no alpha-fucosidase activity in his cultured lymphoblasts. He was found to be homozygous for a Q422X mutation, which resulted in loss of an EcoRI restriction site. The authors stated that no previously reported fucosidosis families with this same homozygous mutation showed dystonia.

Cragg et al. (1997) investigated the molecular basis of the deficiency of alpha-L-fucosidase in 8 patients in whom the diagnosis of fucosidosis had been made on clinical and enzymatic grounds. None of the patients had a deletion or gross alteration of the FUCA1 gene. SSCP analysis followed by direct sequencing of amplified exons and flanking regions identified putative disease-causing mutations in 6 of the 8 patients, who had severe forms of the disease and very low residual fucosidase activity and protein. Five of the 6 mutations had not previously been described.

Willems et al. (1999) reviewed the mutational spectrum of fucosidosis. The 22 mutations that had been detected included 4 missense mutations, 17 nonsense mutations, and 1 splice site mutation. All of these mutations led to nearly absent enzymatic activity and severely reduced cross-reacting immunomaterial. Therefore, the observed clinical variability was considered to be due to secondary unknown factors.

Animal Model
In a dog with alpha-L-fucosidase deficiency, Taylor et al. (1986) found that bone marrow transplantation after total lymphoid irradiation raised the level of enzyme activity in both visceral and neural tissues with consequent reduction in the severity of the storage lesions. These results offered hope that early bone marrow transplantation may prevent the development of disease in neurovisceral storage disorders.

Studying the canine model of fucosidosis in a colony of English springer spaniels, Occhiodoro and Anson (1996) determined the nucleotide sequence and predicted amino acid sequence of canine fucosidase, which showed a high level of identity with the human and rat sequences. The study of the gene in the affected animals demonstrated a 14-bp deletion in mRNA. The deletion created a frameshift and introduced a premature translation termination codon at amino acid 152 and was shown to correspond to a deletion of the last 14 bp of exon 1. Rapid PCR-based screening for the mutation was performed on genomic DNA from dogs within the colony, enabling detection of both carrier and homozygous dogs.

(Note 2)
Fucosidosis. Fucosidosis is an oligosaccharidosis caused by a deficiency of a-L-fucosidase, leading to accumulation and excretion of glycoproteins, glycolipids, and oligosaccharides containing fucoside moieties (Thomas GH, Beaudet AL 1995). It was first described by Durand et al in 1966.

Fucosidosis has autosomal recessive inheritance. It appears to be more common in Southern Italians and in people from the southwestern part of the United Statesムe.g., New Mexican Spanish-Americans, and Navajo (Durand P et al 1979, Willems PJ et al 1991). In a review (Willems PJ et al 1991), 40% of the 45 families reported were consanguineous.

Through in situ hybridization studies, the a-fucosidase 1 gene (FUCA1) was assigned to chromosome 1p34 (Fowler ML et al 1996). Using similar techniques, a pseudogene, FUCA1 P, has been mapped to 2q3 1-q32 (Coucke P et al 1991). The gene structure for human fucosidase includes eight exons spanning 23 kb, and the sequence of the pseudogene is 80% identical to the cDNA (Kretz KA et al 1992). Most mutations have been found in isolated families, suggesting that fucosidosis is due to a large number of different mutations (Seo H-C et al 1993, Lee FA et al 1977, Tiberio G et al 1995, Willems N et al 1999). Traditionally, two phenotypes have been identified: a more severe infantile form referred to as type I, and a milder form, described as type II. In a review of 77 cases (Willems PJ et al 1991), it was suggested that this is an arbitrary separation of a continuum of severity (Thomas GH, Beaudet AL 1995). In addition, mild and severe cases occur within sibships (Willems PJ et al 1988) and among patients who are homozygous for the common Gln to stop mutation at codon 422 (Q422X) (Durand P et al 1966). The major distinguishing features of the milder phenotype are the presence of angiokeratomas, longer survival, and a more normal sodium chloride content of sweat, as compared with the severe form (Thomas GH, Beaudet AL 1995).

Facies.
Patients with a more severe phenotype typically have a progressively coarse facies in the first year of life with large lips, periorbital puffiness, and frontal bossing. There is some resemblance to patients with MPS III. The hair, however, is not as coarse. The tongue may be large. The corneas are clear and the fundi are unremarkable.

Skeletal system.
Patients exhibit growth retardation and dysostosis multiplex. The vertebral bodies are initially ovoid with subsequent flattening, marginal irregularity, and beaking in lateral projection (Brill PW et al 1975, Lee FA et al 1977, Provenzale JM et al 1995). There is mild hypoplasia of the supraacetabular portions of the ilia. Bone trabeculation is coarse.

Central nervous system.
Progressive neurologic deterioration has been reported (Provenzale JM et al 1995). Cranial CT and MRI have shown density and signal abnormalities within the globus pallidus, internal capsules, and periventricular white matter (Provenzale JM et al 1995, Terespolsky D et al 1996). Spasticity, hyperreflexia, and dystonia may be present (George S et al 1994).

Other findings.
Psychomotor retardation, hepatosplenomegaly, cardiomegaly, seizures, and respiratory infections occur frequently but are variable. Tortuous conjunctival vessels and bull's eye retinopathy have been reported (Snodgrass 1976). Kivlin (Peters plus) syndrome has been diagnosed in a single patient (Snodgrass 1976). Angiokeratomas may be present (Fleming C et al 1997, George S et al 1994). Hernias have also been reported.

Oral findings.
Gingival and labial telangiectasias have been reported (Prindiville DE, Stern D 1976).

Laboratory findings.
Peripheral lymphocytes are vacuolated. Skin biopsy shows deposits of homogeneous eosinophilic material between the dermis and epidermis. Electron microscopic studies reveal numerous membrane-bound vacuoles in all tissues (Freitag F et al 1971). Urinary excretion of MPS is normal, but there is excess excretion of fucosyl-containing oligosaccharides. There is a suggestion that fucosidosis types I and II can be distinguished by the Patten of urinary excretion (Ng Ying Kin NM 1987). There is deficient activity of the lysosomal enzyme, a-L-fucosidase in tissues, cultured fibroblasts, leukocytes, serum, and urine (Cragg H et al 1997). Sweat chlorides are markedly increased in the severe form and to a lesser extent in the milder form.

Prenatal diagnosis has been accomplished (Poenaru et al 1976). If the molecular lesion in a specific family has been identified, prenatal diagnosis through DNA analysis can be considered.

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