Metachromatic leukodystrophy異染性腦白質退化症: 幹細胞基因治療案例

自體幹細胞基因移植救活MLD病人 星島日報星島日報港大醫學院公布亞洲首宗利用自體幹細胞基因移植，成功救活一名患有遺傳性異染性腦白質退化症（MLD)台灣藉患者的個案。港大眼科學系及內科學系助理教授表示，自體造血幹細胞能透過基因修復提高ARSA 功能，減低自身免疫力排斥問題。MLD 為罕見疾病，患者因缺乏一種名為芳基硫酸酯酶（ARSA)的物質，導致出現腦神經功能退化，更可於發病後10年內死亡，全球每年新症有約1900人。 亞洲首名接受移植治療的潤潤，今日亦有與母親李碧如到場。李帶淚說，「由於沒先例，在確定要接受治療後曾背負莫大壓力，十分感恩潤潤現在能吃能喝，又開始做運動及上學」。潤潤則笑說，現最希望能幫助其他罕病患者。

港深合醫腦病救寶島少女  [2015-05-21]■廖苡安（左）接受幹細胞基因移植後病情受到控制。 港大供圖  亞洲首宗自體幹細胞「加工回輸」免排斥治療  香港文匯報訊（記者 鮑旻珊）港大醫學院聯同深圳及台灣兩地醫學院成功為一名患有致命性遺傳病的台灣少女，進行亞洲首宗幹細胞介導基因治療，令本來快將失去運動能力，甚至無法自理個人衛生及走路的患者慢慢回復智力，更重獲運動及語言能力，可以重返校園。不過，患者接受治療後，仍要接受長達5年觀察。去年9月，港大李嘉誠醫學院聯同深圳市第二人民醫院及台灣大學醫學院附設醫院，為一名患有異染性腦白質退化症的台灣少女，進行亞洲首宗幹細胞介導基因治療。港大醫學院負責協助造血幹細胞的純化工作及提供基因分析；深圳方面負責患者醫療護理及幹細胞回輸；台灣方面則負責移植後的追蹤工作。異染性腦白質退化症，為致命性遺傳病，全球的發病率為每10萬人就有1.4人至1.8人患病，以嬰兒發病最為常見，其次是青少年。港大李嘉誠醫學院眼科學系及內科學系助理教授連褀周表示，由於疾病屬罕有病，令人警覺意識低，而且早期症狀不明顯，令90%患者錯失早期最佳治療的機會。連褀周續指，患者會出現智力下降、失明、癲癇、四肢癱瘓等，最終喪失運動能力及死亡。一般青少年由發病至死亡，只是10年內的事，小孩更快，發病至癱瘓在1年至2年內發生，甚至在3年至5年死亡。

記性差漸「失語」 赴意求診被拒  現年18歲的廖苡安於2009年時發病，但病徵並不明顯，媽媽李碧如指，女兒開始忘東忘西、賴床等，都是一般小孩都會發生的，故有所忽略。至2012年，女兒的情況轉趨嚴重，「找不到路回家，而且不能說話及食飯，難以表達自己。」遂帶女兒到醫院求診，才確診患上異染性腦白質退化症。李碧如表示，曾到意大利求診，但被拒絕，當地醫生指其女兒的情況太嚴重，狀況已經太差。其後輾轉認識到港大的連褀周醫生，並接受治療。經過治療後，女兒已可重返校園，亦可打理自己個人衛生、幫忙做簡單的家務，更可做運動。

智商能否回復 有待觀察 連褀周指，當時因經評估後，發現廖苡安未完全失明及癱瘓，故仍有治療機會，決定利用該技術治療她，而她接受治療後，仍要接受長達5年觀察。連褀周又稱，患者的智商因患病而受到影響，但治療後能否完全回復，則要經觀察過才可確定。整個治療過程則需要500萬港元。連褀周稱，幹細胞介導基因治療與傳統的技術比較，其中一個好處是因幹細胞是自體得來，不會出現免疫排斥。至於未來成功率及普及化，則仍然有待探討。

Metachromatic leukodystrophy, the most common form of leukodystrophy, is a rare inherited neurometabolic disorder affecting the white matter of the brain (leukoencephalopathy). It is characterized by the accumulation of a fatty substance known as sulfatide (a sphingolipid) in the brain and other areas of the body (i.e., liver, gall bladder, kidneys, and/or spleen). The fatty protective covering on the nerve fibers (myelin) is lost from areas of the central nervous system (CNS) due to the buildup of sulfatide. Symptoms of metachromatic leukodystrophy may include convulsions, seizures, personality changes, spasticity, progressive dementia, motor disturbances progressing to paralysis, and/or visual impairment leading to blindness. Metachromatic leukodystrophy is inherited as an autosomal recessive trait. There are three forms of the disease that have similar symptoms. However, they are distinguished by the age of onset: infantile, juvenile, and adult forms of metachromatic leukodystrophy.

Signs & Symptoms  The early signs and symptoms of metachromatic leukodystrophy may be vague and gradual in onset, making this disorder difficult to diagnose. Subtle changes in thought processing (mentation), memory, and/or posture may be the first symptoms observed in people with this disorder. Occasionally the earliest symptom is a disturbance in vision or numbness somewhere in the body. Late infantile metachromatic leukodystrophy is usually detected in the second year of life, most commonly before the age of 30 months. The initial signs of the late infantile form include irritability, diminished muscle tone, and gait disturbance. Juvenile metachromatic leukodystrophy typically begins between the ages of 4 and 10 years. Adult or late-onset metachromatic leukodystrophy begins after 16 years of age most often during the third or fourth decade. The symptoms of all forms of the disease are similar. However, visual difficulties may be more pronounced in infants, while psychosis and dementia may be more severe in adults with this disease. Symptoms may vary greatly among affected individuals. The symptoms of all forms of metachromatic leukodystrophy may include vision problems leading to blindness, personality changes, and motor disturbances such as clumsiness, muscle weakness (hypotonia), rigidity, inability to coordinate movement (ataxia), and/or muscle spasms especially of the neck, spine, arms, and legs. Other symptoms may include abdominal distention, difficulty speaking (dysarthria), loss of previously acquired intellectual skills, general mental deterioration, and/or seizures. As the symptoms of Metachromatic Leukodystrophy progress, blindness, paralysis, psychosis, and/or dementia may develop. Behavioral abnormalities and dementia are particularly pronounced in the adult-onset form of the disease. Peripheral neuropathy may also occur in individuals with metochromatic leukodystrophy. Peripheral neuropathy is a general term that denotes a disorder of the peripheral nervous system. The peripheral nervous system consists of all the motor and sensory nerves that connect the brain and spinal cord to the rest of the body (i.e., the nerves outside the central nervous system). The symptoms and physical findings associated with peripheral neuropathies may be extremely complex and vary greatly from case to case. Common findings associated with peripheral neuropathy may include muscle weakness; pain; numbness; redness; and/or burning or tingling sensations in the affected areas, especially the arms and legs (extremities).

 

Causes  Metachromatic leukodystrophy is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The symptoms of metachromatic leukodystrophy develop due to a deficiency of the enzyme arylsulfatase A (cerebroside sulfatase), which acts on a certain substance (sulfatide) in the fatty covering on nerve fibers (myelin sheath) of the central nervous system's white matter. The gene that regulates the activity of arylsulfatase A has been located on the long arm of chromosome 22 (22q13.31qter). Low levels of this enzyme lead to the degeneration of the myelin and progressive neurological symptoms. The adult- onset form of this disease occurs because of defects in the protein that activates arylsulfatase activity, even though the quantity of the enzyme may be normal in some affected adults with metachromatic leukodystrophy.

Affected Populations  Metachromatic leukodystrophy is a rare disorder that affects males and females in equal numbers. People of all ethnic backgrounds may be affected by this disease. More than 160 cases have been reported in the medical literature. The prevalence of the late infantile form is 1 in 40,000. The prevalence of the juvenile form is 1 in 150,000. The symptoms of the infantile form of metachromatic leukodystrophy typically begin by the age of two years. Juvenile metachromatic leukodystrophy usually begins between ages 4 and 10 years, and adult or late-onset metachromatic leukodystrophy typically begins after 16 years of age.

Related Disorders Symptoms of the following disorders can be similar to those of metachromatic leukodystrophy. Comparisons may be useful for a differential diagnosis:

Adrenoleukodystrophy is a rare inherited metabolic disorder characterized by the loss of the fatty covering (myelin sheath) on nerve fibers within the brain (cerebral demyelination) and the progressive degeneration of the adrenal gland (adrenal atrophy). Increased levels of very long chain fatty acids (VLCFA) accumulate in the blood plasma and other tissues of the body. The most common form of the disease occurs during childhood. Symptoms may include: behavioral changes such as poor memory, increasingly poor school work, loss of emotional control, and/or dementia. Other symptoms may include the impaired ability to coordinate movement (ataxia), exaggerated reflex responses (hyperreflexia), muscle weakness on one side of the body (hemiparesis), speech difficulties, hearing loss, and/or visual difficulties. (For more information on this disorder, choose "Adrenoleukodystrophy" as your search term in the Rare Disease Database.) Alexander's disease is an extremely rare progressive metabolic disorder that is frequently inherited. It is one of a group of diseases known as the Leukodystrophies. Alexander's disease is characterized by the loss of the fatty layers that cover the nerve fibers. The symptoms of the disorder usually begin during infancy and may include muscle spasms, developmental delays, seizures, and/or mental retardation. When Alexander's disease begins during childhood, the symptoms may include difficulty swallowing, painful joints, vomiting, difficulty breathing, the inability to cough, and/or muscle spasms. (For more information on this disorder, choose "Alexander" as your search term in the Rare Disease Database.) Canavan disease is a rare inherited neurological disorder characterized by spongy degeneration of the brain and spinal cord (central nervous system). Symptoms may include lack of muscle tone (hypotonia), the loss of previously acquired mental, motor, and/or physical skills, poor head control, an abnormally enlarged head (megalocepahly), and/or blindness. Other symptoms may include involuntary muscle contractions of the arms and legs, exaggerated reflex responses, weakness of the muscles that support the head (atonicity), and/or paralysis. Canavan disease is caused by a deficiency of the enzyme aspartoacylase. Symptoms may begin during early infancy and usually progress rapidly, resulting in life-threatening complications. (For more information on this disorder, choose "Canavan" your search term in the Rare Disease Database.) Krabbe's leukodystrophy is a rare inherited metabolic disorder characterized by the abnormal accumulation of a fatty substance (ceremide galactoside) in the brain. Symptoms develop due to a deficiency of the enzyme galactoside beta-galactosidase and may include irritability, vomiting, episodes of partial unconsciousness, and/or seizures. There may also be spastic contractions of the legs, difficulty swallowing, and/or mental deterioration. (For more information on this disorder, choose "Krabbe" as your search term in the Rare Disease Database.) Tay-Sach disease is a rare inherited disorder that results in the progressive destruction of the central nervous system. The body is unable to properly metabolize certain fats (lipids) due to the absence of an enzyme (hexosaminidase A). This results in the accumulation of these fats in the brain (GM2 gangliosidosis). Symptoms may include an abnormal startle response and muscle spasms (myoclonic jerks). Between 6 and 10 months of age, additional symptoms appear including feeding difficulties, muscle weakness (hypotonia), restlessness, unusual eye movements, and red circular spots in the eyes (cherry red macular spots). After 12 months affected children may lose previously acquired skills and coordination. Tay-Sach disease is generally found among children of Eastern European Jewish heritage. (For more information on this disorder, choose "Tay-Sachs" as your search term in the Rare Disease Database.) Sandhoff disease is a rare inherited lipid storage disease resulting in the progressive deterioration of the central nervous system. A deficiency of the enzyme hexosaminidase (beta-subunit) results in the accumulation of certain fats in the brain and other organs of the body. Sandhoff disease is a severe form of Tay-Sachs disease and is not limited to any particular ethnic group. The first symptoms of Sandhoff disease typically begin between the ages of 3 to 6 months and may include feeding problems, general weakness, an exaggerated startle reflex, motor weakness, and/or red spots (cherry macules) in the eyes. Other symptoms may include progressive mental deterioration, spasticity, heart murmurs, seizures (myoclonic and generalized), blindness, and/or an abnormally enlarged spleen. (For more information on this disorder, choose "Sandhoff" as your search term in the Rare Disease Database.) Pelizaeus-Merzbacher brain sclerosis is a rare inherited disease of the central nervous system that is associated with the progressive deterioration of the white matter of the brain. The symptoms may begin during infancy (classical form of the disease) or adulthood. In infants, symptoms may include failure to develop normal control of the head and eyes, growth delays, muscle tremors, weakness, involuntary jerky muscle movements, facial grimacing, unsteadiness, and/or the abnormal permanent fixation of joints (contractures). (For more information on this disorder, choose "Pelizaeus- Merzbacher" as your search term in the Rare Disease Database.)

Standard Therapies  The diagnosis of Metachromatic Leukodystrophy is confirmed by a thorough medical evaluation and laboratory tests. A specialized urine test uses a dye (toluidine blue) to stain certain substances in the urine. The urinary sediment contains material (metachromatic galactosphingosulfatides) that appears red after staining. The levels of protein in the fluid that surrounds the brain and spinal cord (cerebrospinal fluid) are usually elevated. The treatment for Metachromatic Leukodystrophy is symptomatic and supportive. The diagnosis of this disorder in a developing fetus (prenatal testing) is possible by measuring arylsulfatase A activity in cultured cells from the fluid that surrounds the fetus (amniotic fluid). These cells may be obtained during a special procedure during which amniotic fluid is extracted by syringe (amniocentesis) and then analyzed. Genetic counseling will be of benefit for families of children with Metachromatic Leukodystrophy.