(Globoid cell leukodystrophy; GLD; GCL)
(Globoid cell leukoencephalopathy)
(Galactosylceramide beta-galactosidase deficiency)
(Galactosylceramidase deficiency; GALC deficiency)
責任遺伝子：606890 Galactosylceramidase (GALC) <14q31>
Abnormal thumb morphology (母指形態異常) [HP:0001172] 
Aplasia/Hypoplasia of the abdominal wall musculature (腹壁筋無形成/低形成) [HP:0010318] 
Ataxia (運動失調) [HP:0001251] 
Cloverleaf skull (クローバー葉様頭蓋) [HP:0002676] 
EMG abnormality (筋電図異常) [HP:0003457]
Feeding difficulties (食餌摂取障害) [HP:0011968] 
Global developmental delay (全般的発達遅滞) [HP:0001263] 
Sensorineural hearing impairment (感音難聴) [HP:0000407] 
Sensory neuropathy (感覚ニューロパチー) [HP:0000763] 
Spasticity (痙縮) [HP:0001257] 
Visual impairment (視力障害) [HP:0000505] 
Fever (発熱) [HP:0001945] 
Gait disturbance (歩行障害) [HP:0001288] 
Generalized myoclonic seizures (全身性ミオクロニー発作) [HP:0002123] 
Hemiplegia/hemiparesis (片麻痺/片不全麻痺) [HP:0004374] 
Irritability (被刺激性) [HP:0000737] 
Recurrent respiratory infections (反復性呼吸器感染) [HP:0002205] 
Weight loss (体重喪失) [HP:0001824] 
Abnormal flash visual evoked potentials (フラッシュ視覚誘発電位異常) [HP:0007928] 
Autoimmune thrombocytopenia (自己免疫性血小板減少) [HP:0001973] 
Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
Blindness (盲) [HP:0000618] 
CNS demyelination (中枢神経脱髄) [HP:0007305] 
Decerebrate rigidity (除脳拘縮) [HP:0025013] 
Decreased nerve conduction velocity (神経伝導速度減少) [HP:0000762]
Developmental regression (発達退行) [HP:0002376] 
Diffuse cerebral atrophy (びまん性大脳萎縮) [HP:0002506] 
EEG abnormality (脳波異常) [HP:0002353] 
Failure to thrive (成長障害) [HP:0001508] 
Hearing impairment (難聴) [HP:0000365] 
Hydrocephalus (水頭症) [HP:0000238] 
Hyperactive deep tendon reflexes (深部腱反射亢進) [HP:0006801] 
Hypertonia (筋緊張亢進) [HP:0001276] 
Increased CSF protein (髄液中蛋白増加) [HP:0002922]
Motor deterioration (運動悪化) [HP:0002333] 
Muscular hypotonia (筋緊張低下) [HP:0001252] 
Neurodegeneration (神経変性) [HP:0002180] 
Nystagmus (眼振) [HP:0000639] 
Optic atrophy (視神経萎縮) [HP:0000648] 
Peripheral demyelination (末梢脱髄) [HP:0011096] 
Progressive spasticity (進行性痙縮) [HP:0002191] 
Recurrent fever (反復性発熱) [HP:0001954] 
Seizures (けいれん) [HP:0001250] 
Sensorimotor neuropathy (感覚運動ニューロパチー) [HP:0007141] 
Vomiting (嘔吐) [HP:0002013] 
【一般】発症 (3-6か月) =不明熱/*被刺激性/刺激過敏性/ 嘔吐/食餌摂取困難 +/- けいれん →急速に進行性の重度の精神および運動退化
*著明な初期筋緊張亢進 / 深部腱反射亢進 → 反射減弱
【頭】(水頭症, 大頭, 小頭)
【眼】瞳孔反射遅延 / 視神経萎縮→ 盲 (末期で)
異常な flash visual evoked potentials (VEP)
異常な brainstem auditory evoked potentials (BAEP)
【X線】びまん性大脳萎縮 (CT, MRI)
初期は大脳などの深部灰白質と脳室周囲と内包白質の対称性の明瞭な濃い領域 → *後半は白質ジストロフィー
*galactosylceramidase 欠損 (血清, 白血球, 線維芽細胞, 羊水細胞, 絨毛, 固形組織)
蓄積したpsychosine と galactosylceramide を含む脳組織の 'Globoid cells'; galactocerebroside beta-galactosidase 欠損
乳児型：生後6か月以内の発症 (症例の90%; 通常2歳までに死亡する)
(要約) Globoid cell leukodystrophy (Krabbe 病) 球様細胞白質萎縮(症)
Krabbe 病 (Globoid cell leukodystrophy または galactosylceramide lipidosis) は、まれな致死的なことが多い神経系の髄鞘を障害する変性疾患である
デンマークの神経医 Knud Haraldsen Krabbe が命名
(頻度) 約1/100,000 出産, イスラエルのアラブ人で約1/6000
(原因) GALC 遺伝子変異が原因→ galactosylceramidase 不足を生じる
(症状) Krabbe 病の乳児は出生時は正常である
若年発症および成人発症の Krabbe 病もある (類似症状をもつが緩徐進行性)
(診断) 多核球状細胞 (multinucleated globoid cells), 神経脱髄と変性, 脳細胞破壊
ミエリンの特殊染色 (例; luxol fast blue) が診断の助けとなる
クラッベ病（Krabbe disease）は, グロボイド細胞白質ジストロフィー（globoid-cell leukodystrophy; GLD）ともよばれ, ガラクトセレブロシダーゼの欠損により, 中枢の神経線維を形成するオリゴデンドログリアと末梢の神経線維を形成するシュワン細胞の障害から脱随（髄鞘, ミエリンの破壊）を引き起こし, 中枢神経障害と末梢神経障害をきたす常染色体劣性遺伝性疾患である。また, ガラクトセレブロシダーゼのおもな基質であるガラクトセレブロシドは蓄積しないが, 微量な基質のサイコシンが蓄積することにより, 細胞障害を引き起こすと考えられている。
ライソゾーム酵素の一つであるガラクトセレブロシダーゼ（GALC）の遺伝子変異により, 酵素活性が低下し, サイコシンの蓄積を生じる。それにより, 中枢神経のオリゴデンドログリアおよび末梢神経のシュワン細胞を障害し, 脱随を引き起こし, 中枢神経障害と末梢神経障害を呈する。
① 乳児型：生後6ヶ月までに哺乳不良, 易刺激性や首が座らないなどの症状で発症し, 急速に進行し, 1歳までに寝たきりとなり, 2,3歳で死亡することが多い。
② 後期乳児型：生後7ヶ月から3歳で発症し, 易刺激性, 精神運動発達遅滞, 退行を認める。
③ 若年型：4から8歳で失調, 歩行障害, 視力障害を認め, 緩徐に進行する。
④ 成人型：9歳以降に精神症状などで発症し, 5から10年の経過で歩行障害, 認知障害, 視力障害などを認め, 緩徐に進行する。
2. 発症時期により, 4つの病型に分類される。
・乳児型：生後6か月までに発症し, 定頸の不安定, 易刺激性, 哺乳不良などの退行を認め, 急速に進行し, 多くは１歳までに寝たきりとなり, 2−3年で死亡することが多い。
・後期乳児型：生後7か月～3歳で発症し, 易刺激性, 精神運動発達遅滞, 退行を認める。
・若年型：4～8歳で発症し, 歩行障害, 失調, 視力障害などを認め, ゆっくり進行する。
・成人型：9歳以降に精神症状で発症し, 5から10年の経過で歩行障害, 認知障害, 視力障害などがゆっくり進行する。
a. 頭部MRIのT2強調画像やFLAIR（fluid attenuated inversion recovery）法で白質の高信号域を認め, 側脳室後角周囲から広がることが多い。Diffusion法で, 進行部位の高信号域を認めることもある。
b. 髄液検査では, 蛋白の著明な高値, 神経特異エノラーゼ（neuron specific enolase; NSE）の高値を認める。
c. 末梢神経伝導速度では, 上下肢ともに正常の半分以下になることが多い。成人型では軽度のこともある。聴性脳幹反応（auditory brain-stem response; ABR）, 視覚誘発電位（visual-evoked potentials; VEP）で異常を認める。
d. リンパ球や培養皮膚線維芽細胞のガラクトセレブロシダーゼ（galactocerebrosidase; GALC）活性低下を認める。
e. 遺伝子解析でGALC遺伝子に変異を認め, 一部の表現型の推定が可能。
f. 除外診断として, 血中極長鎖脂肪酸（副腎白質ジストロフィーの鑑別）やリンパ球中のアリルスルファターゼA（arylsulfatase A; ARSA）活性の測定（異染性白質ジストロフィーの鑑別）を行うことが望ましい。
疑診：上記臨床症状に, a, bかつcを認めれば強く疑う。fで副腎白質ジストロフィーや異染性白質ジストロフィーを否定できればより強く疑う。
根本的治療として, 発症早期の造血幹細胞移植は有効であるが, 適応に関しては慎重に検討すべきである。その他は, 対症療法が中心で, 抗痙攣薬, 経管栄養や人工呼吸管理が必要となることがある。
病型により様々で, 乳児型は2, 3歳までに寝たきりとなるが, 若年型や成人型は緩徐に進行する。
病型や造血幹細胞移植の施行の有無によりかなり異なるが, 対症療法の中でも胃食道逆流症に対する噴門形成術や胃瘻造設術, 呼吸障害に対する気管切開, 喉頭分離術や声門閉鎖術などの外科的治療の適応は慎重に検討すべきである。
また, 成人型では, 歩行障害のみで発症する例もあり, 進行も緩徐なため, 診断に時間がかかり注意を要する。
(Comment) galactosylceraminidase deficiency in serum, leukocytes, fibroblasts, amniotic fluid cells, chorioni villi, solid tissues
(Responsible gene) *606890 Galactosylceramidase (GALC) <14q31.3>
.0001 Krabbe disease (245200) [GALC, GLU385TER [dbSNP:rs121908010] (Sakai et al. 1994)
.0002 Krabbe disease [GALC, 30-KB DEL, IVS10] (Rafi et al. 1995; De Gasperi et al. 1996; Kleijer et al. 1997; Tappino et al. 2010)
.0003 Krabbe disease [GALC, ASP544ASN [dbSNP:rs387906952] (Rafi et al. 1996)
.0004 Krabbe disease [GALC, ILE599SER [dbSNP:rs387906953] (Rafi et al. 1996)
.0005 Krabbe disease [GALC, GLY553ARG] (Tappino et al. 2010)
.0006 Krabbe disease [GALC, IVS13DS, G-A, +1] (Tappino et al. 2010)
.0007 Krabbe disease [GALC, 1-BP DEL, 1901T] (Tappino et al. 2010)
.0008 Krabbe disease [GALC, GLY286ASP [dbSNP:rs199847983] (Tappino et al. 2010)
.0009 Krabbe disease [GALC, PRO318ARG [dbSNP:rs387906954] (Tappino et al. 2010)
.0010 Krabbe disease [GALC, GLY41SER [dbSNP:rs387906955] (Fiumara et al. 2011)
A number sign (#) is used with this entry because Krabbe disease is caused by homozygous or compound heterozygous mutation in the galactosylceramidase gene (GALC; 606890) on chromosome 14q31.
Krabbe disease is an autosomal recessive lysosomal disorder affecting the white matter of the central and peripheral nervous systems. Most patients present within the first 6 months of life with 'infantile' or 'classic' disease manifest as extreme irritability, spasticity, and developmental delay (Wenger et al., 2000). There is severe motor and mental deterioration, leading to decerebration and death by age 2 years. Approximately 10 to 15% of patients have a later onset, commonly differentiated as late-infantile (6 months to 3 years), juvenile (3 to 8 years), and even adult-onset forms. The later-onset forms have less disease severity and slower progression. These later-onset patients can be clinically normal until weakness, vision loss and intellectual regression become evident; those with adult onset may have spastic paraparesis as the only symptom. Disease severity is variable, even within families (summary by Tappino et al., 2010).
Hofman et al. (1987) described cherry red spots in an infant with Krabbe disease who died at age 18 months. Spots were subtle but evident at age 13 months and became prominent at 17 months. Zlotogora and Cohen (1987) pointed to protruding ears as a dysmorphic feature of Krabbe disease. Their report concerned a total of 11 affected children seen in Israel, all of Arab origin and 4 from related Druze families. Lyon et al. (1991) reviewed 50 cases.
Tappino et al. (2010) reported 30 unrelated patients with Krabbe disease ascertained over a 30-year period. Twenty-one patients had the infantile form, with onset between 1 and 5 months of age. Four patients had onset between 8 and 11 months, 4 had onset around 4 years of age, and 1 had adult onset at age 26 years. Those with the infantile and late-infantile forms presented with psychomotor regression, muscular hypertonia and spasticity, truncal hypotonia, and irritability; 2 had seizures, and 2 had nystagmus. Brain imaging, when performed, showed white matter changes and/or hypomyelination, and 6 patients had calcifications. Peripheral nerve conduction velocities were slowed. Residual GALC enzyme activity ranged from 0 to 22% of normal.
In a retrospective analysis of 26 Italian or Tunisian patients with Krabbe disease, Fiumara et al. (2011)found that 9 (34%) had the classic early-infantile form with onset before age 6 months. All but 1 were born of consanguineous parents; family history of another child adopted from Brazil was not available. All presented between 2 and 5 months of age with unprovoked inconsolable crying, opisthotonus, and hemiplegia. There was rapid progressive motor deterioration with generalized hypertonia and hyperreflexia. Four patients had horizontal nystagmus, 7 had optic nerve atrophy, and 4 had seizures. Brain MRI showed symmetric cerebral and cerebellar demyelination, as well as changes in the basal nuclei and corpus callosum. Generalized brain atrophy with dilatation of the ventricles and subarachnoideal spaces was evident later over the course of the disease. GALC activity levels ranged between 0.39 and 5.8% of normal. Death occurred between 6 and 29 months of age.
Suzuki (1972) described 2 patients with morphologically and enzymatically proven Krabbe disease who survived into childhood and into the teens. Crome et al. (1973) also described a 'late-onset' variety.
From complementation studies by somatic cell hybridization, Loonen et al. (1985) concluded that the early infantile and later onset forms of GLD are allelic. They proposed that there are 2 later onset forms: a late infantile or early childhood form, and a late childhood or juvenile form.
Kolodner (1989) described several cases with a later onset, the oldest case in his experience being that of an 84-year-old woman. Phelps et al. (1991) reported 4 cases with later onset--at ages 4 years and 9 months, 8 years, 5 years, and 5 years. Two of the patients were sibs; the 2 others were each born of a consanguineous mating. One of the patients, although showing minor abnormalities at age 5, was not evaluated medically until the age of 16 and was still working as a baker at the age of 19 years.
Verdru et al. (1991) described globoid cell leukodystrophy in a 19-year-old daughter of consanguineous parents. Clinical examination showed postural tremor of the right upper limb, pyramidal paresis of the left lower limb, and extensive plantar responses bilaterally. There were no signs of peripheral nerve involvement or intellectual impairment when she was first seen. By 9 months later, however, the signs had progressed and there was clinical evidence of peripheral nerve involvement. The patient had almost complete deficiency of galactosylceramide beta-galactosidase. A brother had had normal psychomotor development until the age of 14 months, when he began to have a toppling gait. He became progressively spastic and blind, developed seizures, and died at the age of 4 years.
Kolodny et al. (1991) reviewed the clinical and biochemical features of 15 cases of late-onset Krabbe disease. Turazzini et al. (1997) described 2 brothers with adult-onset Krabbe disease. A 39-year-old man presented with a 2-year history of persisting unsteadiness of gait with weakness of the legs. A younger brother, 29 years old, was asymptomatic but showed tetra-hyperreflexia with bilateral ankle clonus. Both brothers showed MRI changes of demyelination in the white matter of the brain, while nerve conduction was completely normal. Both patients showed deficiency of galactosylceramide beta-galactosidase comparable to that found in the infantile form.
Tappino et al. (2010) reported that 3 of 4 patients with juvenile onset presented with gait disturbances and frequent falls due to spasticity and ataxia, and the fourth presented with decreased visual acuity. Brain imaging showed white matter changes, and 2 had decreased peripheral nerve conduction velocities. Residual GALC enzyme activity ranged from 0 to 13% of normal. One man presented at age 26 years with gait disturbances, frequent falls, and spasticity; he had 5% residual GALC enzyme activity.
In a retrospective analysis of 26 Italian or Tunisian patients with Krabbe disease, Fiumara et al. (2011)found that 17 (66%) had the late-onset form, including 6 with late-infantile, 9 with early-juvenile, and 2 with adult onset. Fourteen of the patients came from the same area of Sicily, north of Catania. Nine patients died between 6 and 12 years. The first signs were hemiplegia in 12 and visual impairment in 3, followed by rapid deterioration in motor abilities within 3 to 24 months. All patients showed white matter abnormalities at onset, affecting the parietooccipital areas, corpus callosum, and corticospinal tracts, with later involvement of the internal and external capsules, subcortical U fibers, pyramidal tracts, and brainstem. Four patients showed impairment of the auditory and visual evoked potentials. Six of 12 patients studied showed mixed demyelinating and axonal sensorimotor neuropathy. Molecular studies showed that 4 patients were homozygous for a founder G41S mutation (606890.0010), and 4 were compound heterozygous for G41S and another mutation. Three of those homozygous were alive in their forties, although significantly handicapped; 1 had onset at age 3 years and 2 had onset at age 23 years. The fourth homozygous patient had onset at age 4 years and was alive at age 27. There was no correlation between age at onset, disease severity, genotype, and GALC enzyme activity, which ranged from 1 to 6% among those homozygous for G41S. However, considering the whole study, presence of the G41S mutation was associated with a more protracted disease course.
Husain et al. (2004) reported neurophysiologic studies of 20 patients with early-onset Krabbe disease and 6 patients with late-onset Krabbe disease. Of early-onset patients, all had abnormal nerve conduction studies (NCS), 88% had abnormal brainstem auditory evoked potentials (BAEP), 65% had abnormal EEG, and 53% had abnormal flash visual evoked potentials (VEP). Of late-onset patients, 20% had abnormal nerve conduction studies, 40% had abnormal BAEP, 33% had abnormal EEG, and all had normal flash VEP. The abnormalities correlated well with disease severity measured by MRI.
Siddiqi et al. (2006) found that 25 of 27 children with Krabbe disease, aged 1 day to 8 years, showed abnormal motor and/or sensory nerve conduction studies with uniform slowing of conduction velocities. Motor and sensory responses were abnormal in 82% of patients. The severity of the demyelination on NCS correlated with clinical severity of the disease. There were no conduction blocks, indicating uniform rather than focal demyelination of peripheral nerves. Marked NCS abnormalities were found in a 1-day-old and 2 3-week-old neonates, indicating that peripheral neuropathy occurs very early in Krabbe disease and that nerves are likely affected even in intrauterine life. Siddiqi et al. (2006) concluded that nerve conduction studies are a sensitive tool to screen for Krabbe disease. In an accompanying paper, Siddiqi et al. (2006) found that nerve conduction studies improved in 7 (60%) of 12 patients after hematopoietic stem cell transplantation followed for an average of 18 months. However, some patients showed further decline after an initial improvement. There was greater improvement if the transplant was performed earlier in life.
Krabbe disease is an autosomal recessive disorder. First-cousin parents were noted by Van Gehuchten (1956). Nelson et al. (1963) observed 3 affected sibs. Arroyo et al. (1991) described Krabbe disease in all 3 of monozygotic triplets.
Although deficiency of cerebroside-sulfatide sulfotransferase was earlier reported in Krabbe disease (Bachhawat et al., 1967), Suzuki and Suzuki (1970) found deficiency of galactocerebroside beta-galactosidase which they thought was etiologic and better accounted for the morphologic and biochemical features of the disorder. Suzuki and Suzuki (1971) demonstrated an intermediate level of activity of galactocerebroside beta-galactosidase in serum, white cells, and fibroblasts of heterozygotes.Young et al. (1972) found deficiency of the same enzyme, galactocerebrosidase, in a case with late onset.
D'Agostino et al. (1963) concluded that the initial histologic manifestation of the disease is the presence of PAS-positive material extracellularly and cerithin in microglial cells, which later appear as globoid cells. Definitive diagnosis of this disorder, which clinically can be so similar to several other encephalopathies of infancy, is made by finding these characteristic 'globoid cells' in brain tissue (Martin et al., 1981). These cells, derived from monocyte-macrophage stem cells of the bone marrow, contain accumulated psychosine as well as galactosylceramide.
Wenger and Louie (1991) discussed pseudodeficiency of galactocerebrosidase comparable to the pseudodeficiency of arylsulfatase A (250100); both are hard to distinguish from the bona fide GALC deficiency which may signify a presymptomatic person who will present with adult-onset clinical disease.
Harzer et al. (1987) demonstrated the feasibility of prenatal enzymatic diagnosis using chorionic villi.Harzer and Schuster (1989) warned against the use of uncultured chorionic villi in the prenatal enzymatic diagnosis; this material is subject to uncontrolled contamination with maternal enzyme.
Krivit et al. (1998) reported on their experience using allogeneic hematopoietic stem cell transplantation in the treatment of Krabbe disease. They treated 5 children, 1 with the infantile type and 4 with late-onset disease. Four of the patients had clinical CNS abnormalities before transplantation. In all 4 cases, CNS deterioration was reversed. In the patient with the infantile form of the disease, the expected decline in CNS function had not occurred by the age of 16 months, 14 months posttransplantation. The authors concluded that CNS manifestations of Krabbe disease can be reversed or prevented by allogeneic hematopoietic stem cell transplantation.
Escolar et al. (2005) assessed the safety and efficacy of transplantation of umbilical cord blood from unrelated donors in 11 asymptomatic newborns and 14 symptomatic infants with infantile Krabbe disease. All were prepared with myeloablative chemotherapy. The rates of donor-cell engraftment and survival were 100% and 100%, respectively, among the asymptomatic newborns and 100% and 43%, respectively, among symptomatic infants. Surviving patients showed durable engraftment of donor-derived hematopoietic cells with restoration of normal blood galactocerebrosidase levels. Infants who underwent transplantation before the development of symptoms showed progressive central myelination and continued gains in developmental skills, and most had age-appropriate cognitive function and receptive language skills, but a few had mild to moderate delays in expressive language and mild to severe delays in gross motor function. Children who underwent transplantation after the onset of symptoms had minimal neurologic improvement.
Wang et al. (2011) described the ACMG standards and guidelines for the diagnostic confirmation and management of presymptomatic individuals with lysosomal storage diseases.
Studies by Zlotogora et al. (1990) showed that the Krabbe disease mutation is located on human chromosome 14. Zlotogora et al. (1990) undertook linkage analysis with RFLPs, focusing first on chromosome 17, based on a study by Lyerla et al. (1989). When no evidence of linkage was found there, they took advantage of the homology between the mouse and human chromosomes: the 'twitcher' mouse mutation results in an autosomal recessive leukodystrophy that is similar histopathologically to Krabbe disease (Duchen et al., 1980). Sweet (1986) found that the 'twitcher' locus is on mouse chromosome 12, a chromosome that has large regions of homology with human chromosome 14. A multipoint lod score of 3.40 was found with marker D14S24 (14q21-q31). Cannizzaro et al. (1994)mapped the GALC gene (606890) to chromosome 14q31.
In a study in Catania in Sicily, Fiumara et al. (1990) found that 7 of 10 cases seen in a 12-year period were of the late infantile form, suggesting an unusually high frequency of the gene in Sicily. Of the 7 with the late infantile form, 2 were sibs born of first-cousin parents and 1 of the others was the product of a first-cousin marriage.
Zlotogora et al. (1985) found a frequency of 6 per 1,000 live births in a large Druze isolate in Israel. The isolate numbered about 8,000 persons. The Druze religion dates from the 11th century when it was founded in Egypt with subsequent expansion into Syria and Lebanon.
In 2 different inbred communities in Israel with Krabbe disease, Rafi et al. (1996) identified 2 different founder mutations in the GALC gene: 1 in a Moslem Arab population (606890.0003) and 1 in a Druze population (606890.0004).
Tappino et al. (2010) noted that the median prevalence of Krabbe disease is estimated to be about 1 in 100,000 (1.0 x 10(-5)) with wide variations between countries: 1.35 in the Netherlands, 1.21 in Portugal, 1.00 in Turkey, 0.71 in Australia, and 0.40 in Czech Republic.
Sakai et al. (1994) identified homozygosity for a nonsense mutation in the GALC gene (606890.0001) in a patient with typical Krabbe disease.
Rafi et al. (1995) analyzed the GALC gene in 2 patients with infantile Krabbe disease and identified homozygosity for a 30-kb deletion (606890.0002) that was found to be associated with a 502C-T transition on the same allele, which they designated '502/del.' The transition was determined to be a polymorphism. Rafi et al. (1995) studied an additional 46 patients with infantile Krabbe disease and identified 8 who were homozygous for the 502/del allele and 5 who were compound heterozygotes for 502/del allele and a second mutant allele, including 3 missense mutations and 1 single nucleotide insertion, which had not yet been confirmed by expression studies.
De Gasperi et al. (1996) analyzed the GALC gene in 9 families with late-onset GLD and in 1 patient with classic Krabbe disease. They reported that 5 of the patients were compound heterozygotes for the deletion (606890.0002) first reported by Rafi et al. (1995) and another mutation in the GALC gene. De Gasperi et al. (1996) also identified 6 missense mutations, 1 nonsense mutation, and an insertion in the GALC gene. Most of the novel mutations identified appeared to be private family mutations.
In a review of the molecular genetics of Krabbe disease, Wenger et al. (1997) stated that more than 40 mutations had been identified in patients with all clinical types of globoid cell leukodystrophy.
Among 30 unrelated Italian patients with Krabbe disease, Tappino et al. (2010) identified 33 different mutations in the GALC gene, including 14 novel mutations (see, e.g., 606890.0005-606890.0009). The 15 novel mutations included 4 missense mutations in highly conserved residues, 7 frameshift mutations, 3 nonsense mutations, and 1 splice site mutation. Thus, 73% of the newly described mutations were expected to affect mRNA processing. In silico analysis predicted that the missense mutations had a high probability of being deleterious. The common 30-kb deletion (606890.0002) accounted for 18% of mutant alleles, and 4 patients had a founder mutation (G553R; 606890.0005). Otherwise, most of the mutations were private. There were no clear genotype-phenotype correlations, but some missense mutations were associated with milder phenotypes (see, e.g., G286D; 606890.0008).
De Gasperi et al. (1996) noted that it was not always possible to make conclusions about the phenotype from the genotype. Most difficult to explain was the phenotype of 5 late-onset patients who carried on both alleles mutations that completely abolished enzyme activity. They concluded that these observations point to the possibility that other genetic factors besides mutations in the galactocerebrosidase gene may contribute to the phenotype in late-onset GLD. Wenger et al. (1997)noted that some mutations clearly resulted in the infantile type if found in homozygous state or in compound heterozygous state with another severe mutation, but it is difficult to predict the phenotype of novel mutations or mutations found in apparent heterozygous state (when a second mutated allele has not been identified). A high frequency of polymorphic changes on apparent disease-causing alleles also complicated the interpretation of the effects of mutations. The molecular characterization of the naturally occurring mouse, dog, and monkey models will permit their use in therapeutic trials.
In a review of GALC mutations causing Krabbe disease, Furuya et al. (1997) found that those in the adult-onset form occurred in the N- or C-terminus, whereas those in the infantile form occurred in the central domain.
Xu et al. (2006) investigated mutations of the GALC gene in 17 unrelated Japanese patients with Krabbe disease and reviewed the mutations previously reported in 11 Japanese patients. The authors found that 12del3ins and I66M + I289V, which had been identified only in Japanese individuals to date, accounted for 37% of the mutant alleles; with 2 additional mutations, G270D and T652P, these accounted for up to 57% of mutations in Japanese patients. Xu et al. (2006) observed a tendency for the I66M + I289V, G270D, and L618S mutations to be associated with a mild phenotype.
In a retrospective analysis of 26 patients with Krabbe disease, Fiumara et al. (2011) found that 17 (66%) had the late-onset form, including 6 with late-infantile, 9 with early-juvenile, and 2 with adult onset. Fourteen of the patients came from the same area of Sicily, north of Catania. Molecular studies showed that 4 patients were homozygous for a founder G41S mutation (606890.0010), and 4 were compound heterozygous for G41S and another mutation. There was no correlation between age at onset, disease severity, genotype, and GALC enzyme activity, which ranged from 1 to 6% among those homozygous for G41S. However, considering the whole study, presence of the G41S mutation was associated with a more protracted disease course.
A somewhat similar disorder was described in 3 adult sibs by Ferraro (1927), but this may be a genetically distinct condition. See discussion of Menkes (1963) and of Norman et al. (1961). Korn-Lubetzki and Nevo (2003) provided an interesting history of the first descriptions of Krabbe disease byKrabbe (1916) and others.
Duchen et al. (1980) described an autosomal recessive leukodystrophy of the mouse, 'twitcher,' which is very similar histopathologically and may be homologous. Kobayashi et al. (1980) demonstrated that the 'twitcher' mouse is an enzymatically authentic model of human GLD, as are disorders in sheep and dog. Igisu and Suzuki (1984) studied the 'twitcher' mouse.
Ichioka et al. (1987) studied the effects of bone marrow transplantation in the twitcher mouse.Hoogerbrugge et al. (1988) showed that transplantation of enzymatically normal congenic bone marrow in the twitcher mouse results in increased galactosylceramidase levels in the CNS. There was a gradual disappearance of globoid cells, the histologic hallmark of Krabbe disease, and the appearance of foamy macrophages capable of metabolizing the storage product. By immunohistochemical labeling, it was shown that these macrophages in the CNS were of donor origin. Extensive remyelination was observed in the CNS. In further studies, Hoogerbrugge et al. (1988) found that bone marrow transplantation in the twitcher mouse resulted in an increase in the galactosylceramidase activity in the CNS to 15% of normal donor levels with a prevention of paralysis of the hind legs and a prolonged survival from 30-40 days to more than 100 days in some instances.
In addition to the 'twitcher' mouse, West Highland white terriers and Cairn terriers have a naturally occurring form of Krabbe disease (Victoria et al., 1996). Wenger et al. (1999) showed successful transduction of cultured skin fibroblasts from a West Highland white terrier with GLD and normal canine bone marrow, using a retroviral vector containing the human GALC cDNA.
Tohyama et al. (2000) crossbred twitcher mice with acid beta-galactosidase knockout mice (GM1-gangliosidosis; 230500) and found that the acid beta-galactosidase gene dosage exerts an unexpected and paradoxical influence on the twitcher phenotype. Twitcher mice with an additional complete deficiency of acid beta-galactosidase (galc-/-, bgal-/-) had the mildest phenotype among twitcher mice of all genotypes, with the longest life span and nearly rescued central nervous system pathology. In contrast, twitcher mice with a single functional acid beta-galactosidase gene (galc-/-, bgal+/-) had the most severe disease, with the shortest life span and brain levels of psychosine even higher than those of twitcher mice. The double knockout mice showed a massive accumulation of lactosylceramide in all tissues as expected, but only a half-normal amount of galactosylceramide in brain. The authors hypothesized that the acid beta-galactosidase gene may function as a modifier gene for the phenotypic expression of galactosylceramidase deficiency.
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