Mannosidosis, beta A, lysosomal
(Lysosomal beta-mannosidase deficiency)
(Beta-mannosidase deficiency)

マンノース症, βA, リソソーム
指定難病19 ライソゾーム病
小児慢性特定疾病 代82 マンノシドーシス

責任遺伝子:609489 Mannosidase, beta A, lysosomal (MANBA) <4q24>

 Abnormal facial shape (顔貌異常) [HP:0001999] [0401]
 Hearing impairment (難聴) [HP:0000365] [091]
 Hypoplasia of the abdominal wall musculature (腹壁筋低形成) [HP:0005247] 1200]
 Intellectual disability (知的障害) [HP:0001249] [0120]
 Recurrent respiratory infections (反復性呼吸器感染) [HP:0002205] [014230]
 Seizures (けいれん) [HP:0001250] [01405]
 Demyelinating peripheral neuropathy (脱髄性末梢ニューロパチー) [HP:0007108] [0201]
 Abnormality of metabolism/homeostasis (代謝-ホメオスターシス異常) [HP:0001939]
 Aggressive behavior (攻撃的行動) [HP:0000718] [02200]
 Angiokeratoma (被角血管腫) [HP:0001014] [2302]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Generalized hypotonia (全身性筋緊張低下) [HP:0001290] [0242]
 Hyperactivity (多動) [HP:0000752] [02204]
 Increased urinary disaccharide excretion (尿中二糖類排泄増加) [HP:0012066]
 Neurological speech impairment (神経学的発語障害) [HP:0002167] [023]
 Recurrent infections (反復性感染症) [HP:0002719] [01423]
 Tortuosity of conjunctival vessels (結膜血管蛇行) [HP:0000503] [0652]

【一般】正常な発達 → 精神遅滞
 けいれん (まれ)
 Gilles de la Tourette 症候群 (1例)
【神経】協調運動障害 (18 か月で)
 脱髄性末梢ニューロパチー, 進行性 (まれ)
 母指球筋成長障害 (まれ)
【検査】beta-mannosidase 活性低下 (血漿, 線維芽細胞, 白血球)
 尿中二糖類増加 (mannosyl-N-acetylglucosamine)

<小児慢性特定疾病 代82 マンノシドーシス>
糖蛋白質の糖鎖を加水分解するリソソ-ム酵素の中で,アルファ結合した終末mannoseを加水分解するのはα-mannosidase(LAMAN, EC3.2.1.24),ベータ結合した終末mannoseを加水分解するのはβ-mannosidase(MANBA, EC3.2.1.25)と呼ばれる。それぞれの酵素欠損による疾患をα-mannosidosis(OMIM #248500), β-mannosidosis(OMIM #248510)と呼んでいる.α-mannosidase遺伝子(MAN2B1)は19p13.2-q12に,β-mannosidosis遺伝子(MANBA)は4q21-25にマップされ,いずれも常染色体劣性遺伝形式をとる.大変稀な疾患であり, 国内報告は殆どない。
共通した臨床症状としては, 粗野な顔貌,多発性骨異形成,高身長,精神発達遅延,退行,肝脾腫, 角膜混濁,白内障(特徴的な棘状白濁),難聴などを乳児期から幼児期にかけて認める.
1)α-mannosidosisには臨床的に乳児型(type I)と若年成人型(type II)に分類されるが,その中間型もある。乳児型は生後3カ月から1歳までに精神運動発達遅延,筋力低下,肝脾腫,易感染性,粗野な顔貌,dysostosis multiplex(多発性骨異形成)などに気付かれる.その他に突背,関節拘縮,角膜混濁,白内障(棘状白濁),難聴,巨舌などを認める.若年成人型は1-4歳頃までに精神運動発達遅延,難聴などで発症する軽症型であり,進行も乳児型に比し緩徐である。 
2)β-mannosidosisにも重症度に差があるが,典型的には1-6歳までに精神運動発達遅延を認めるが,粗野な顔貌, dysostosis multiplexは軽度であり,他に易感染性,難聴,被角血管腫などを伴う。
リンパ球の空胞化(ただしβ-mannosidosisにおいては認めない), 尿中mannose含有物質の薄層クロマトグラフィー分析, 汎血球減少症,低ガンマグロブリン血症などが診断に有用な臨床症状である。確定診断は白血球, 皮膚線維芽細胞におけるα/β-mannosidase活性の測定で可能である。またそれぞれの遺伝子検査が可能である。
臨床所見 (上記), 生化学分析, および遺伝子解析に基づいて行う。
・臨床検査;リンパ球の空胞化(ただしβ-mannosidosisにおいては認めない), 尿中mannose含有物質の薄層クロマトグラフィー分析, 汎血球減少症,低ガンマグロブリン血症
・確定診断;白血球, 皮膚線維芽細胞におけるα-mannosidase活性の測定が確定診断となる.
全A  疾患名に該当する場合
重症度にもよるが, 支持療法が中心であり, 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。

(Responsible gene) *609489 Mannosidase, beta A, lysosomal (MANBA) <4q24>
.0001 Beta-mannosidosis (248510) [MANBA, IVS-AS, A-G, -2] (Alkhayat et al. 1998)
.0002 Beta-mannosidosis [MANBA, IVS7, A-G, +1] (Uchino et al. 2003)
.0003 Beta-mannosidosis [MANBA, 10-BP INS, NT562] (Sedel et al. 2006)
.0004 Beta-mannosidosis [MANBA, IVS13AS, G-A, -1] (Sedel et al. 2006)
.0005 Beta-mannosidosis [MANBA, SER505PRO] (dbSNP:rs121434334) (Riise Stensland et al. 2008)
.0006 Beta-mannosidosis [MANBA, 375A-G] (Riise Stensland et al. 2008)
.0007 Beta-mannosidosis [MANBA, GLU83TER] (dbSNP:rs121434335) (Bedilu et al. 2002)
.0008 Beta-mannosidosis [MANBA, GLN426TER] ((dbSNP:rs121434336) Bedilu et al. 2002)
.0009 Beta-mannosidosis [MANBA, 2-BP DEL, 1541AT] (Bedilu et al. 2002)

*MANBA: Mannosidase, beta A, lysosomal (879 amino acids)
・glycosyl hydrolase 2 ファミリーのメンバーである
・N-linked glycoprotein oligosaccharide 異化径路での最後の exoglycosidase のあるリソソームに局在する
・全てのN-linked glycoprotein oligosaccharidesの非還元末端の単一の beta-linked mannose 残基を分割する exoglycosidase である

A number sign (#) is used with this entry because beta-mannosidosis (MANSB) is caused by homozygous or compound heterozygous mutation in the gene encoding beta-mannosidase (MANBA;609489) on chromosome 4q.

Beta-mannosidosis is an autosomal recessive lysosomal storage disease of glycoprotein catabolism caused by a deficiency of lysosomal beta-mannosidase activity. The most severely affected patients show developmental delay and mental retardation, but there are differing levels of severity and some patients may have comparatively mild disease (Bedilu et al., 2002) The disorder was first described in goats (Jones and Dawson, 1981), who have a more severe neurodegenerative disorder than that seen in humans.

Clinical Features
Wenger et al. (1986) described a 46-month-old boy with a severe deficiency in beta-mannosidase activity, whose parents had an intermediate level of enzyme consistent with autosomal recessive inheritance. Beta-mannosidase activity levels near zero were found in all available samples from the patient, including leukocytes, plasma, and cultured skin fibroblasts. In addition to the deficiency of beta-mannosidase, this patient also had a low level of heparin sulfamidase activity in cultured skin fibroblasts. The patient's urine contained excess disaccharide that was identified as mannosyl(1-4)-N-acetylglucosamine and heparan sulfate. The patient showed coarsening facial features, mild bone disease, delayed speech development, hyperactivity, and mental retardation. Many of the findings resembled those found to have defects in the catabolism of the oligosaccharide chains of glycoproteins such as fucosidosis (230000), sialidosis (256550), and aspartylglucosaminuria (208400). The deficiency of heparin sulfamidase and the excess of heparan sulfate in the urine, both findings consistent with Sanfilippo syndrome type A (252900), suggested the presence of 2 disorders. Hu et al. (1990) used complementation studies to show that the patient reported by Wenger et al. (1986) had both Sanfilippo syndrome and beta-mannosidosis.

Cooper et al. (1986) reported an Indian-Hindu man with beta-mannosidosis; his parents were not related. Intellectual impairment was first observed when the patient began to attend school. Clinical assessment at the age of 44 years showed mental retardation but no other neurologic signs; CT scan of the brain was normal. The patient had angiokeratomas on the scrotum and the shaft of the penis and marked tortuosity of conjunctival vessels. He did not have facial dysmorphism, hepatosplenomegaly, or radiologic changes of the bones. The urine was free of albumin, red cells, and casts. The patient's 19-year-old mentally retarded brother had similar skin lesions. Both brothers had deficiency of beta-mannosidase, and the parents had intermediate levels. Cooper et al. (1988) found markedly decreased beta-mannosidase activity in plasma, white cells, fibroblasts, and urine obtained from the 2 affected Indian brothers (the younger brother was stated to be 29 years old); all other lysosomal enzymes measured, including sulfamidase, showed normal activity. Biopsy of a skin lesion from the 'bathing trunk' area showed marked cytoplasmic vacuolization. Urinary mucopolysaccharide excretion was normal, but thin-layer chromatography of urinary oligosaccharides showed an abnormal band shown to be a disaccharide. Cooper et al. (1988) noted that the difference in storage material in the caprine disease may account for the clinical differences; a trisaccharide accumulates in the goat.

By analyzing urinary oligosaccharides and by measuring enzyme activity in leukocytes and plasma, Dorland et al. (1988) diagnosed beta-mannosidosis in 2 sons of a first-cousin Turkish couple. Behavioral abnormalities and deafness with speech retardation were the main clinical features. Kleijer et al. (1990) reported 2 affected sibs from a Czech Gypsy family with beta-mannosidosis. The girl was severely affected; an older brother had milder manifestations. Heterozygous levels of beta-mannosidase were found in the fibroblasts and/or plasma of the parents and a sister. Cooper et al. (1991) reported a female infant with severe beta-mannosidosis. She had no dysmorphic features except brachycephaly. She showed moderate developmental delay, developed refractive seizures at age 12 months, and died at age 15 months. Urinary analysis showed mannose disaccharides.

Poenaru et al. (1992) described a case in which speech impairment was the first symptom of infantile onset. The patient had mental retardation, recurrent infections, hyperactivity, and mild facial dysmorphism. Beta-mannosidase activity was completely lacking in the patient and a heterozygous level was found in the parents. Mannosyl-N-acetylglucosamine was identified in the patient's urine.

In a black African 14-year-old boy, Levade et al. (1994) described severe deficiency of beta-mannosidase activity manifested by bilateral thenar and hypothenar amyotrophy, electrophysiologically demonstrable demyelinating peripheral neuropathy, and cytoplasmic vacuolation of skin fibroblasts and lymphoid cells. The authors cited reports of 10 patients in 7 families.

Rodriguez-Serna et al. (1996) described a 22-year-old woman who since the age of 12 years had progressive angiokeratoma affecting the lower limbs and buttocks, with no other abnormalities. Enzyme studies revealed beta-mannosidase deficiency in cultured fibroblasts and in serum and leukocytes. The patient's parents exhibited intermediate enzyme levels, confirming autosomal recessive inheritance. Rodriguez-Serna et al. (1996) stated that a total of 11 cases of beta-mannosidase deficiency occurring in 8 families had been reported. Mental retardation and neurologic disorders were present in most reported patients.

Sedel et al. (2006) reported an 18-year-old male patient with beta-mannosidosis who exhibited motor and vocal tics since childhood, attention deficit, hyperactivity, impulsivity, and aggressiveness consistent with Gilles de la Tourette syndrome (GTS; 137580). He also had bilateral hearing loss and mild cognitive impairment. Molecular analysis identified compound heterozygosity for 2 mutations in the MANBA gene (609489.0003 and 609489.0004).

Molecular Genetics
In 2 affected sibs from a Czech Gypsy family with beta-mannosidosis reported by Kleijer et al. (1990), Alkhayat et al. (1998) identified a homozygous null mutation in the MANBA gene (609489.0001).

In 2 patients with beta-mannosidosis, an Indian Hindu man originally reported by Cooper et al. (1986) and a Turkish woman originally reported by Wijburg et al. (1992), Bedilu et al. (2002)identified compound heterozygosity and homozygosity, respectively, for null mutations in the MANBA gene (608489.0007-608489.0009). Bedilu et al. (2002) noted that disease presentation in patients with null mutations is variable: the Czech Gypsy sibs described by Kleijer et al. (1990) had facial dysmorphism and skeletal involvement, whereas the Indian Hindu man and his affected younger brother did not have those features, and the Turkish woman had no apparent dysmorphology at 5 years of age but developed epicanthus, broad nasal bridge, and coarse facies by 18 years of age as well as a unilateral hip abnormality. Bedilu et al. (2002) concluded that beta-mannosidosis in humans may be milder than typical of other lysosomal storage disorders.

In a patient of European descent with severe beta-mannosidosis previously reported by Poenaru et al. (1992), Riise Stensland et al. (2008) identified compound heterozygosity for 2 mutations in the MANBA gene (609489.0005 and 609489.0006). Riise Stensland et al. (2008) stated that 20 patients from 16 families had been reported.

Animal Model
In goats, deficiency of beta-mannosidase causes a severe disorder that affects peripheral and central nervous system myelin, resulting in tremor, nystagmus, ataxia, and early death (Jones and Dawson, 1981; Malachowski and Jones, 1983; Lovell and Jones, 1983; Jones et al., 1983). Indeed, the caprine disorder was thoroughly described several years before the human disorder as a severe neurologic disease with CNS demyelination and early death. Although several laboratories sought the human equivalent, it was not found until 1986. Bovine beta-mannosidosis was reported in 1991 in neonatal Salers calves in North America and New Zealand (Jones and Abbitt, 1993).

Leipprandt et al. (1996) identified a single-base deletion at position 1398 in the beta-mannosidase DNA isolated from a goat with beta-mannosidosis. This deletion resulted in a shift in the reading frame and premature termination of translation, yielding a deduced peptide of 481 amino acids. Affected animals were homozygous for the mutation and obligate carriers were heterozygous. The assay for the presence or absence of the mutation was used for prenatal diagnosis using DNA collected from fetal fluids. The assay also confirmed chimerism in a goat with an atypically mild beta-mannosidosis phenotype.

Zhu et al. (2006) reported that Manba-null mice were viable, fertile, and showed no differences in general appearance or behavior from wildtype mice at over 12 months of age. Histologic evidence of storage material, manifest as intracytoplasmic vacuoles, was present in several organs, including epididymis, liver, kidney, and thyroid, although the accumulated amounts were small. All Manba-null animals examined had cytoplasmic vacuolation in the central nervous system, but there was variation in severity and distribution. Affected areas included pyramidal cells in the dorsolateral cerebral cortex, choroid plexus, hippocampus, and spinal cord, among others. The storage material was a disaccharide, similar to that found in humans with beta-mannosidosis. Biochemical studies showed that the mutant mice had increased alpha-mannosidase activity. The clinical and biochemical phenotype was distinct from that seen in ruminants.

(Note 2)
Deficiency of beta-mannosidase was well known in goats and cattle (Jones MZ, Dawson G 1981) as a severe neurologic disease associated with dysmyelination of the central nervous system and early death before the first human patient was reported in 1986 (Cooper A et al 1986). The first mutation associated with human beta-mannosidosis was reported in a study (Alkhayat AH et al 1998) of 2 sibs with different manifestations of beta-mannosidosis described by Kleijer et al (1990). The gene for, B-mannosidase was mapped to 4q22-q25 by study of a panel of rodent/human somatic cell hybrid lines (Alkhayat AH et al 1998). There appears to be homozygosity for an A-to-G transition 2 bp upstream of a splice acceptor site. Lysosomal beta-mannosidase has been cloned (Chen H et al 1995). Inheritance of beta-mannosidosis is autosomal recessive; the frequency is not yet known. Patients of different ethnic backgrounds have been reportedムe.g., Hindu (Cooper A et al 1986) and Turkish (Dorland L et al 1988) patients. A goat model has been described (Jones MZ, Dawson G 1981). Upper and lower respiratory tract infections are frequent.

There is a coarsening of facial features.

Central nervous system.
Most patients are normal in the first few months of life; eventually all have mental retardation. In the most severe phenotype, status epilepticus at age 12 months with quadriplegia and death at 15 months have been reported (Cooper A et al 1991). Speech is impaired (Poenaru L et al 1992). Aggressive or unstable behavior has been described. Brain atrophy has been demonstrated by CT scan in a severely affected patient (Cooper A et al 1991). Peripheral neuropathy has been documented in a number of patients (Levade T et al 1994).

Eyes and ear.
Hearing loss and ear infections are common.

Musculoskeletal system.
Skeletal abnormalities occur but are not usual (Kleijer WJ et al 1990).

Other findings.
Hepatosplenomegaly has not been described, but angiokeratomas have been reported (Cooper A et al 1986, Rodriguez-Sema M et al 1996).

Laboratory aids.
Cytoplasmic vacuoles have been noted on skin biopsy but not in lymphocytes or bone marrow cells. Slight vacuolization and granulation of bone marrow cells were reported in another patient (Cooper A et al 1991). A disaccharidase containing mannose and N-acetylglucosamine is the major abnormal component found in the urine of beta-mannosidosis patients (Thomas GH, Beaudet AL 1995).

Definitive diagnosis of beta-mannosidosis is made by measuring the activity of beta-mannosidase in leukocytes or cultured fibroblasts (Thomas GH, Beaudet AL 1995). Prenatal diagnosis can be carried out (Kleijer WJ et al 1992).

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(3) Lovell KL, Jones MZ: Distribution of central nervous system lesions in beta-mannosidosis. Acta Neuropath 62: 121-126, 1983
(4) Malachowski JA, Jones MZ: Beta-mannosidosis: lesions of the distal peripheral nervous system. Acta Neuropath 61: 95-100, 1983
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(6) Wenger DA et al. Human beta-mannosidase deficiency. New Eng J Med 315: 1201-1205, 1986
(7) Lundin L-C: A gene (Bmn) controlling beta-mannosidase activity in the mouse is located in the distal part of chromosome 3. Biochem Genet 25: 603-610, 1987
(8) Cooper A et al. Human beta-mannosidase deficiency: biochemical findings in plasma, fibroblasts, white cells and urine. J Inherit Metab Dis 11: 17-29, 1988
(9) Dorland L et al. Beta-mannosidosis in two brothers with hearing loss. J Inherit Metab Dis 11 (suppl. 2): 255-258, 1988
(10) Kleijer WJJr et al. Beta-mannosidase deficiency: heterogeneous manifestation in the first female patient and her brother. J Inherit Metab Dis 13: 867-872, 1990
(11) Van Pelt J et al. Clin Chim Acta 187: 55-60, 1990
(12) Cooper A et al: Beta-mannosidase deficiency in a female infant with epileptic encephalopathy.J Inherit Metab Dis 14:18, 1991
(13) Kleijer WJ et al: Prenatal analyses in a pregnancy at risk for beta-mannosidosis. Prenat Diagn 12: 841 -843, 1992
(14) Poenaru L et al. Human beta-mannosidosis: a 3-year-old boy with speech impairment and emotional instability. Clin Genet 41: 331-334, 1992
(15) Wijburg, H.; de Jong, J.; Wevers, R.; Bakkeren, J.; Trijbels, F.; Sengers, R. : Beta-mannosidosis and ethanolaminuria in a female patient. Europ. J. Pediat. 151: 311 only, 1992
(16) Jones MZ, Abbitt B. Animal model of human disease: bovine beta-mannosidosis. Am J Path 142: 957-960, 1993
(17) Levade T et al. Human beta-mannosidase deficiency associated with peripheral neuropathy. Ann Neurol 35: 116-119, 1994
(18) Chen H et al: Molecular cloning and characterization of bovine beta-mannosidase. J Biol Chem 270:3841-3848, 1995
(19) Thomas GH, Beaudet AL: Disorders of glycoprotein degradation and structure: alpha-mannosidosis, beta-mannosidosis, fucosidosis, sialidosis, aspartylglucosaminuria, and carbohydrate-deficient glycoprotein syndrome. In: The Metabolic Basis of Inherited Disease, 7th ed, Scriver CR et al (eds), McGraw-Hill, New York, 1995, pp 2537-2s39
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(21) Rodriguez-Serna M et al. Angiokeratoma corporis diffusum associated with beta-mannosidase deficiency. Arch. Derm. 132: 1219-1222, 1996
(22) Alkhayat AH et al. Human beta-mannosidase cDNA characterization and first identification of a mutation associated with human beta-mannosidosis. Hum. Molec. Genet. 7: 75-83, 1998
(23) Bedilu, R.; Nummy, K. A.; Cooper, A.; Wevers, R.; Smeitink, J.; Kleijer, W. J.; Friderici, K. H. : Variable clinical presentation of lysosomal beta-mannosidosis in patients with null mutations. Molec. Genet. Metab. 77: 282-290, 2002
(24) Uchino, Y.; Fukushige, T.; Yotsumoto, S.; Hashiguchi, T.; Taguchi, H.; Suzuki, N.; Konohana, I.; Kanzaki, T. : Morphological and biochemical studies of human beta-mannosidosis: identification of a novel beta-mannosidase gene mutation. Brit. J. Derm. 149: 23-29, 2003
(25) Sedel, F.; Friderici, K.; Nummy, K.; Caillaud, C.; Chabli, A.; Durr, A.; Lubetzki, C.; Agid, Y. : Atypical Gilles de la Tourette syndrome with beta-mannosidase deficiency. Arch. Neurol. 63: 129-131, 2006
(26) Zhu, M.; Lovell, K. L.; Patterson, J. S.; Saunders, T. L.; Hughes, E. D.; Friderici, K. H. : Beta-mannosidosis mice: a model for the human lysosomal storage disease. Hum. Molec. Genet. 15: 493-500, 2006
(27) Riise Stensland, H. M. F.; Persichetti, E.; Sorriso, C.; Hansen, G. M; Bibi, L.; Paciotti, S.; Balducci, C.; Beccari, T. : Identification of two novel beta-mannosidosis-associated sequence variants: biochemical analysis of beta-mannosidase (MANBA) missense mutations. Molec. Genet. Metab. 94: 476-480, 2008