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Background
The mucopolysaccharidoses are a group of inherited metabolic diseases that are caused by the absence or malfunctioning of specific enzymes needed to break down molecules called glycosaminoglycans, which are long chains of sugar carbohydrates in human cells that help build bone, cartilage, tendons, corneas, skin, and connective tissue. Individuals with a mucopolysaccharidosis (MPS) either do not produce enough of one of the 11 enzymes required to break down sugar chains into proteins and simpler molecules or they produce enzymes that do not work properly, resulting in permanent, progressive cellular damage affecting the individual's appearance, physical abilities, organ and system functioning. In most cases, mental development is also affected. An estimated one in every 25,000 babies born in the United States will have some form of the mucopolysaccharidoses. They are autosomal recessive disorders, meaning that only individuals inheriting the defective gene from both parents are affected. (The exception is MPS II, or Hunter syndrome, in which the mother alone passes along the defective gene to a son.) When both people in a couple have the defective gene, each pregnancy carries with it a one in four chance that the child will be affected. The parents and siblings of an affected child may have no sign of the disorder. Unaffected siblings and select relatives of a child with one of the mucopolysaccharidoses may carry the recessive gene and could pass it to their own children (NINDS, 2013). MPS V, which was also referred to as Scheie syndrome, is a designation which is no longer in use (Dekabon et al, 1976).
Mucopolysaccharidoses I (Hurler's syndrome)
Hurler's syndrome causes progressive deterioration of the central nervous system and death in childhood.
Staba and co-workers (2004) examined the feasibility of using cord blood transplants from unrelated donors and a myeloablative preparative regimen that did not involve total-body irradiation (TBI) in young children with Hurler's syndrome. A total of 20 children with Hurler's syndrome were given conditioning regimens before receiving cod blood transplants from unrelated donors. The children were subsequently evaluated for engraftment, side effects, and effects on disease symptoms. Cord blood donors were discordant for up to 3 of 6 HLA markers. Neutrophil engraftment occurred a median of 24 days after transplantation. Five patients had grade II or grade III acute GVHD; none had extensive chronic GVHD. Seventeen of the 20 children were alive a median of 905 days after transplantation, with complete donor chimerism and normal peripheral blood alpha-L-iduronidase activity (event-free survival rate of 85 %). Transplantation improved neurocognitive performance and decreased somatic features of Hurler's syndrome. The authors concluded that cord blood from unrelated donors appears to be an excellent source of stem cells for transplantation in patients with Hurler's syndrome. Sustained engraftment can be achieved without TBI. They stated that cord blood transplantation favorably altered the natural history of Hurler's syndrome and thus may be important to consider in young children with this form of the disease.
Boelens et al (2007) analyzed data on Hurler's syndrome patients transplanted in Europe to identify the risk factors for graft failure. These investigators compared outcomes of 146 Hurler's syndrome patients transplanted with various conditioning regimens and grafts. Risk factor analysis was performed using logistic regression. "Survival" and "alive and engrafted" rates after first HSCT were 85 % and 56 %, respectively. In multi-variable analysis, T-cell depletion (odds ratio [OR] 0.18; 95 % CI: 0.04 to 0.71; p = 0.02) and reduced-intensity conditioning (OR 0.08; 95 % CI: 0.02 to 0.39; p = 0.002) were the risk factors for graft failure. Busulfan targeting protected against graft failure (OR 5.76; 95 % CI: 1.20 to 27.54; p = 0.028). No difference was noted between cell sources used (bone marrow, peripheral blood stem cells, or UCB); however, significantly more patients who received UCB transplants had full-donor chimerism (OR 9.31; 95 % CI: 1.06 to 82.03; p = 0.044). The authors concluded that cord blood increased the likelihood of sustained engraftment associated with normal enzyme levels and could therefore be considered as a preferential cell source in HSCT.
Hansen et al (2008) reported transplant outcomes following a reduced intensity, highly immunosuppressive preparative regimen in 7 patients with Hurler's syndrome. A total of 6 patients received grafts from unrelated donors and 1 received a sibling donor graft. The preparative regimen was well-tolerated. All patients had initial donor engraftment at 100 days; 1 patient had delayed loss of donor chimerism. There was no severe acute graft versus host disease. Six of the 7 children survived a median of 1,014 days (726 to 2,222 days) post-transplant. The authors concluded that this reduced intensity preparative regimen has the potential to support engraftment and improve survival and outcome in patients with Hurler's syndrome undergoing HSCT.
Sauer et al (2009) stated that allogeneic HSCT can achieve long-term survival in patients with Hurler's syndrome by correcting the enzymatic deficiency. In an attempt to improve long-term engraftment and to reduce regimen-related toxicity (RRT), these investigators used a fludarabine-based TBI-free preparative regimen. A total of 12 children were studied. Median age at HSCT was 14 months (range of 4 to 31 months). CD34 positively selected peripheral blood hematopoietic stem cell were used in 10 children with a matched unrelated donor. Two children with a matched sibling donor received non-manipulated bone marrow. Donor lymphocyte infusions were given in 6/12 children for mixed hematopoietic chimerism. At a median follow-up of 29 months (range of 2 to 85 months), all children engrafted and had either stabilized or improved neurological function. In total, 12/12 patients showed donor-derived engraftment with 9/12 having full and 3/12 having mixed hematopoiesis. One developed acute GVHD greater than or equal to grade II; RRT greater than or equal to grade II was observed in 2 patients.
Guidelines from the International Consensus Panel on the Management and Treatment of Mucopolysacchardosis I (Muenzer et al, 2009) stated that when it is successful, HSCT using either bone marrow or UCB cells can prevent and/or reverse many but not all of the clinical features of severe MPS I. It must be performed early in the disease course, before developmental deterioration begins.
Mucopolysaccharoidosis II (Hunter syndrome)
Hunter syndrome, an X-linked, recessive, lysosomal storage disease, is caused by a defect of the iduronate-2-sulfatase gene. It is diagnosed in approximately 1 out of 65,000 to 132,000 births. In the absence of sufficient enzyme activity, glycosaminoglycans (GAG) accumulate in the lysosomes of many tissues and organs; thus contributing to the multi-system (e.g., cardiovascular, musculo-skeletal, nervous, and respiratory systems) progressive pathologies in these patients. Hunter syndrome usually becomes apparent in children 1 to 3 years of age. Symptoms include growth delay, joint stiffness, and coarsening of facial features. In severe cases, patients experience neurological deficits, enlargement of the liver and spleen, cardiac as well as respiratory problems, and death.
Guffon et al (2009) evaluated the effect of bone marrow transplant (BMT) in children with Hunter syndrome. A total of 8 boys (aged 3 and 16 years) received BMT. In 6 cases, the donor was a sibling with identical HLA status, in 1 case the donor was unrelated but HLA-compatible, and in 1 case the donor was unrelated and mis-matched. Successful engraftment was achieved in all patients, with the proportion of donor cells reaching greater than or equal to 95 % 1 month after transplantation in all patients. Patients were followed for 7 to 17 years and all were still alive, except for 1 boy who died at the age of 10 from unrelated causes. Cardiovascular abnormalities stabilized in all patients, hepato-splenomegaly resolved, and joint stiffness improved, perceptual hearing defects remained stable, and transmission hearing defects improved. Only 1 child required subsequent surgery to correct kyphosis. Neuropsychological outcome was variable and appeared to be related to the severity of the syndrome.
Mucopolysaccharidosis III (Sanfilippo syndrome)
Sanfilippo syndrome (MPS III) causes severe neurological symptoms, including progressive dementia, aggressive behavior, hyperactivity, seizures, some deafness and loss of vision, and an inability to sleep for more than a few hours at a time. MPS III affects children differently, and its progress will be faster in some than in others. Affected children show a marked decline in learning between ages 2 and 6, followed by eventual loss of language skills, and in some children an inability to speak at all. MPS III is also characterized by loss of some or all hearing. Aggressive behavior, hyperactivity, profound dementia, and irregular sleep may make Children, particularly those who retain normal physical strength, may be difficult to manage due to aggressive behavior, hyperactivity, profound dementia, and irregular sleep. As the disease progresses, children become increasingly unsteady on their feet. Most are unable to walk by age 10 with height growth ceasing. Also, thickened skin and mild changes in facial features, bone, and skeletal structures become noticeable with age. Children with MPS III may also experience narrowing of the airway passage in the throat and enlargement of the tonsils and adenoids, making it difficult to eat or swallow, and recurring respiratory infections are common. There are four distinct types of MPS III, due to alteration of a different enzyme for breakdown of the heparin sulfate sugar chain. Although there is little differentiation clinically between the four types, children with type A present with more severe symptoms and progress more quickly. Some individuals with MPS III may live into their teenage years, or even into their twenties or thirties (NINDS, 2013).
Sanfilippo syndrome (MPS III) causes severe neurological symptoms, including progressive dementia, aggressive behavior, hyperactivity, seizures, some deafness and loss of vision, and an inability to sleep for more than a few hours at a time. MPS III affects children differently, and its progress will be faster in some than in others. Affected children show a marked decline in learning between ages 2 and 6, followed by eventual loss of language skills, and in some children an inability to speak at all. MPS III is also charactgerized by loss of some or all hearing. Aggressive behavior, hyperactivity, profound dementia, and irregular sleep may make Children, particularly those who retain normal physical strength, may be difficult to manage due to aggressive behavior, hyperactivity, profound dementia, and irregular sleep. As the disease progresses, children become increasingly unsteady on their feet. Most are unable to walk by age 10 with height growth ceasing. Also, thickened skin and mild changes in facial features, bone, and skeletal structures become noticeable with age. Children with MPS III may also experience narrowing of the airway passage in the throat and enlargement of the tonsils and adenoids, making it difficult to eat or swallow, and recurring respiratory infections are common. There are four distinct types of MPS III, due to alteration of a different enzyme for breakdown of the heparin sulfate sugar chain. Although there is little differentiation clinically between the four types, children with type A present with more severe symptoms and progress more quickly. Some individuals with MPS III may live into their teenage years, or even into their twenties or thirties (NINDS, 2013).
Mucopolysaccharoidosis IV (Morquio syndrome)
MPS IV, also known as Morquio syndrome, has an estimated occurance of one in every 200,000 births, with an onset between the ages 1 and 3. Neurological complications include spinal nerve and nerve root compression resulting from extreme, progressive skeletal changes, conductive hearing loss, neurosensitive hearing loss, and clouded corneas. If hydrocephalus develops and is not treated intelligence can be adversely affected but is otherwise normal. Physical growth slows and often stops around age 8 with skeletal abnormalities including a bell-shaped chest, a flattening or curvature of the spine, shortened long bones, and dysplasia of the hips, knees, ankles, and wrists. In more severe cases of MPS IV children may not live beyond their twenties or thirties (NINDS, 2013).
Mucopolysaccharidosis VI (Maroteaux -Lamy syndrome
MPS VI, Maroteaux-Lamy syndrome, does not affect normal intellectual development but includes many of the physical symptoms found in severe MPS I. MPS VI, which has a variable spectrum of severe symptoms, is caused by the deficient enzyme N-acetylgalactosamine 4-sulfatase,. Neurological complications include pain caused by compressed or traumatized nerves and nerve roots, clouded corneas, deafness, and thickening of the dura. Growth stops suddenly around age 8 and by age 10 children have developed a shortened trunk, crouched stance, and restricted joint movement. Children with MPS VI may also, in severe cases, develop a protruding abdomen and forward-curving spine. These skeletal changes are progressive and limit movement. Most children with MPS VI have some form of heart disease, usually involving valve dysfunction (NINDS, 2013).
Mucopolysaccharidosis VII (Sly syndrome)
MPS VII, also known as Sly syndrome, is one of the least common forms of the mucopolysaccharidoses, with an estimated occurance of fewer than one in 250,000 births. In its rarest form, MPS VII causes children to be born with hydrops fetalis, in which extreme amounts of fluid are retained in the body, and in these cases survival is usually a few months or less. Most children with MPS VII are less severely affected, but do experience neurological symptoms including mild to moderate mental retardation by age 3, communicating hydrocephalus, nerve entrapment, corneal clouding, and some loss of peripheral and night vision. These children often present with short stature, skeletal irregularities, joint stiffness, and umbilical and/or inguinal hernias, and may experience repeated bouts of pneumonia during their first years of life, and generally live into the teenage or young adult years (NINDS, 2013).
The NINDS "Mucopolysaccharidoses fact sheet" (NINDS, 2013) states that BMT and UCB transplantation are high-risk procedures and are usually performed only after family members receive extensive evaluation and counseling.
Adrenoleukodystrophy
Adrenoleukodystrophy (ALD), an X-linked disorder which more severely affects males, is caused by a defect in the metabolism of long-chain fatty acids resulting in demyelination, neurological deterioration, and death. The majority of patients with ALD suffer from adrenal insufficiency, the neurological symptoms can appear either in childhood or adulthood. Childhood ALD, which is the most severe form of this disease, results in onset of neurological symptoms between ages 4 and 10. These symptoms include visual loss, hearing loss, learning disabilities, seizures, speech impairment, dysphagia, increased pigmentation of the skin, challenges in ambulation, abnormal withdrawal or aggression, poor memory and school performance, fatigue, and progressive dementia (NINDS, 2013).
Shapiro et al (2000) examined if bone marrow transplantation (BMT) can stop the progressive demyelination and neurodegeneration of patients with childhood-onset cerebral X-linked ALD (CCALD). A total of 12 patients were followed for 5 to 10 years after BMT. Electrophysiological, neurological, and neuropsychological studies, magnetic resonance imaging (MRI), as well as plasma very-long-chain fatty acid (VLCFA) measurements were used to evaluate the effect of BMT. Magnetic resonance imaging showed improvement in 1.patient and complete reversal of abnormalities in 2 patients. One patient showed no change from baseline to last follow-up. All 8 patients who showed an initial period of continued demyelination stabilized and remained unchanged thereafter. In 10 patients, motor function remained normal or improved after BMT. Verbal intelligence remained within the normal range for 11 patients; performance (non-verbal) abilities were improved or were stable in 7 patients. Decline in performance abilities followed by stability occurred in 5 patients. Plasma VLCFA concentrations decreased by 55 % and remained slightly above the upper limits of normal. The authors noted that 5- to 10-year follow-up of 12 patients with CCALD showed the long-term beneficial effect of BMT when the procedure is done at an early stage of the disease.
Beam et al (2007) evaluated outcomes of unrelated donor umbilical cord blood (UCB) transplantation after chemotherapy-based myeloablative conditioning and retrospectively determined if baseline studies correlated and helped to predict outcome. A total of 12 boys with X-linked ALD who lacked HLA-matched related donors were studied. Baseline studies of neuroimaging, neurophysiological, as well as neurodevelopmental status were performed and patients were subsequently evaluated for engraftment, graft-versus-host disease (GVHD), neurodevelopmental outcomes, and survival. A substudy evaluated whether baseline neuroimaging and neurophysiological studies correlated with cognitive and motor function and if these studies were predictive of post-transplantation outcomes. The UCB grafts had normal levels of VLCFA. Three patients had grade II to IV acute GVHD; 2 had extensive chronic GVHD. Cumulative incidence of overall survival of the group at 6 months was 66.7 % (95 % confidence interval [CI]: 39.9 % to 93.3 %). Median follow-up was 3.3 years (range of 12 days to 6.3 years). As previously reported with BMT, symptomatic patients faired poorly with lower survival and rapid deterioration of neurological function. This study included 3 patients transplanted at a very young age (2.6 to 3.5 years) before the onset of clinical symptoms who continue to develop at a normal rate for 3 to 5 years post-transplant. Although baseline Loes scores correlated with cognitive and motor outcome, neurophysiological studies failed to show statistically significant differences. The authors concluded that transplantation of boys with X-linked ALD using partial HLA-matched UCB yielded similar results to those previously reported after BMT. Superior outcomes were seen in neurologically asymptomatic boys less than 3.5 years of age at the time of transplantation.
Mahmood and colleagues (2007) analyzed survival of CCALD patients who had not received HCT; and (ii) in a subgroup with early cerebral disease, compared survival in those who underwent HCT with those who did not. Retrospective survival analyses were done on 283 CCALD patients who had not received HCT, focusing on a 30-member early stage cerebral subgroup whose neurological disability and MRI severity scores matched those of a 19-member transplanted subgroup previously reported. A Kaplan-Meier survival curve and log-rank test were used for survival analysis and for estimating the difference between the survival probabilities of the groups with statistical significance set at p = 0.05. Mean age at onset of symptoms in the 283 non-transplanted group was 7 years (standard deviation [SD] = 2 years). A total of 131 (SD = 46 %) patients died during the mean follow-up period of 5.9 years (SD = 5.3) at a mean age of 12.3 years (SD = 4.9). The 5-year survival was 66 %; the 5-year survival probability of 54 % in the early stage group was significantly poorer (chi(2) = 7.47, p = 0.006) than the 5-year survival of 95 % in the transplanted group with early stage cerebral disease. The authors concluded that HCT done in the early and progressive stages of CCALD is beneficial, and these findings supported the recommendation that transplantation be offered to patients in the early stages of CCALD.
Miller et al (2011) presented findings on 60 boys who had undergone HSCT with varying conditioning regimens and allograft sources for cerebral ALD between 2000 and 2009. The median age at time of HSCT was 8.7 years with 50% demonstrating a Loes radiographic severity score ≥ 19 and 62% showing clinical evidence of neurologic dysfunction. Survival at a median 3.7 years after HSCT was 78% (n=47). Five year survival estimates for boys with Loes score < 10 at time of HSCT was 89% and for boys with a Loes score ≥ 10 at time of HSCT was 60% (p = .03). Among study participants who had not demonstrated clinical cerebral disease at the time of HSCT, the 5 year survival was 91% and for study participants who had exhibited neurologic dysfunction the 5 year survival was 66% (p = .08). Cumulative mortality incidence 100 days post HSCT was 8%. Thus, the investigators concluded that post-transplantation progression of neurologic dysfunction depended significantly on the pre-HSCT Loes score and clinical neurologic status.
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