Successful unrelated bone marrow transplantation in two siblings with alpha-mannosidosis

Yesilipek AM, Akcan M, Karasu G, Uygun V, Kupesiz A, Hazar V. Successful unrelated bone marrow transplantation in two siblings with alpha-mannosidosis. Abstract: Alpha-mannosidosis is a rare lysosomal storage disorder with an autosomal recessive inheritance. Deficient alpha-mannosidase activity leads to lysosomal accumulation of mannose-rich oligosaccharides. The disease characterized by mental retardation, skeletal changes, hearing impairment, and recurrent infections. Stem cell transplantation has been shown to be an effective treatment. It works by providing increased levels of α-mannosidase in the localized extracellular milieu to provide improvements in skeletal malformations, neurocognitive, and sensorineural function. In this case report, we describe a pair of siblings with α-mannosidosis who successfully underwent HSCT from matched unrelated donors. In both siblings, enzyme levels reached to normal limits and improvements in clinical symptoms were recognized early after HSCT. We conclude that HSCT should be considered as a therapeutic approach in patients with alpha-mannosidosis before disease-related complications have developed.     

Bone marrow transplantation in the treatment of alpha-mannosidosis.

Bone marrow transplantation was performed in a patient with alpha-mannosidosis. To our knowledge this is the first time such treatment has been attempted. The patient died 18 weeks after successful grafting and specimens of tissues were obtained at necropsy. Alpha-mannosidase activity in spleen and liver was just below normal (spleen 102 mumol/g/hour, control 113-330; liver 29 mumol/g/hour, control 30-131). Splenic alpha-mannosidase activity was indistinguishable from the control enzyme with respect to the Michaelis constant, heat stability, and inhibition by cobalt ions, as was 86% of the liver enzyme. In brain tissue alpha-mannosidase activity was 7% of controls, and less than one third had the properties of the normal enzyme. Oligosaccharides were present only in small amounts in liver and spleen, whereas they were greatly increased in brain tissue. Electron microscopic pictures of liver and spleen tissue showed normal morphology, but brain tissue showed definite vacuolation. These findings suggest that transplantation reversed the somatic changes of alpha-mannosidosis but did not affect lysosomal storage within brain tissue. It is concluded that marrow transplantation may not be a suitable treatment for alpha-mannosidosis.     

强烈化疗和自体外周血造血干细胞移植及维甲酸治疗晚期神经母细胞瘤

目的 探讨强烈化疗、自体造血干细胞移植及维甲酸对晚期神经母细胞瘤的治疗效果方法 研究Ⅳ期神经母细胞瘤患儿6例,年龄4～8岁,发病时间1个月～1年;原发部位腹部5例、胸部1例,均有骨髓转移,1例有多发性骨转移及球后病变。成立多学科参与的治疗小组,采用术前化疗、手术切除、强烈化疗、局部放疗、自体外周血造血干细胞移植及维甲酸生物治疗等。结果 经综合治疗造血干细胞移植前6例均达到完全缓解,骨髓中肿瘤细胞消失,骨转移及球后病变被控制。化疗中骨髓抑制明显,血象恢复较慢,达3～4周。感染明显,三分之一疗程后发热,用头孢他定(商品名复达欣)、亚胺培南(商品名泰能)等感染被控制。造血干细胞移植过程顺利。术后随诊4～18个月疾病处于完全缓解状态,心、肝、肾器官功能正常,骨髓恢复正常或在恢复中。结论 强烈化疗、自体外周血造血干细胞移植及维甲酸是治疗Ⅳ期神经母细胞瘤的有效方法。     

Successful implantation of a cochlear implant in a four-yr-old boy after kidney transplantation: A case report

Abstract:  Sensorineural hearing loss is common in children with chronic renal insufficiency. The implantation of a CI is performed routinely in children with profound sensorineural hearing loss. A feared complication is a local infection with subsequent meningitis. Because of this risk, a successful implantation of a CI in children under immunosuppression after kidney transplantation has yet to be described. A four-yr-old boy with congenital renal dysplasia and posterior urethral valves, who was successfully transplanted with a kidney from his father at the age of two and a half yr, is presented. The boy had profound bilateral hearing loss before transplantation, most likely due to ototoxic antibiotic medication and long-term furosemide use. A hearing aid was insufficient; therefore, a CI was performed 20 months after the transplantation and no complications occurred in the 24 months of follow-up. This is the first report of a successful CI in a child after kidney transplantation.     

Alpha-mannosidosis and mutational analysis in a Turkish patient

We present a case of alpha-mannosidosis with its mutational analysis. She was referred to our hospital with the provisional diagnosis of mucolipidosis. She was the first child of second-degree relative parents. She had a coarse face with flat and wide nasal bridge, hepatosplenomegaly, umbilical hernia, lumbar gibbus, motor and mental retardation and deafness. On peripheral blood smear, lymphocytes revealed vacuoles and neutrophils contained some granules resembling Reilly bodies seen in mucopolysaccharidosis (MPS). Based on these findings, the diagnosis of alpha-mannosidosis was suspected. Her urine oligosaccharide chromatography showed an abnormal pattern with a heavy trisaccharide band. Enzyme studies on white cells confirmed a deficiency of alpha-mannosidase activity, which was 2.6 micromol/g/hr. Her DNA analysis showed a S453Y mutation.     

Tissue typing for hematopoietic cell transplantation: Newer techniques and newer antigens for which cross-matching is helpful

Abstract:  Refinements in human leukocyte antigen (HLA) typing techniques for hematopoietic cell transplantation (HCT) have permitted a more precise assessment of donor-recipient histocompatibility, which has impacted transplantation outcomes. More recently, differences in transplant outcomes associated with killer immunoglobulin-like receptor compatibility have emphasized the potential importance of natural killer (NK) cell typing in HCT. This article reviews the current state of the art for HCT donor selection based on both HLA and NK cell typing.     

Time course of recovery of adrenal function in children treated for leukemia

OBJECTIVE: Many protocols for treating children with early B-cell lineage acute lymphoblastic leukemia use 28 consecutive days of high-dose glucocorticoids during induction therapy. We prospectively studied the effects of this therapy on adrenal function. STUDY DESIGN: Ten children with early B-cell lineage acute lymphoblastic leukemia were evaluated by cosyntropin (corticotropin (1-24)) stimulation testing before initiation of dexamethasone therapy and every 4 weeks thereafter until adrenal function returned to normal. RESULTS: All 10 patients had normal adrenal function before dexamethasone treatment and insufficient adrenal responses 24 hours after completing therapy. Each child felt ill for 2 to 4 weeks after completing therapy. Although 7 patients recovered normal adrenal function after 4 weeks, 3 patients did not have normal adrenal function until 8 weeks after discontinuing therapy. Statistically significant differences in both basal and corticotropin-stimulated cortisol levels were noted when comparing tests performed at baseline, 24 hours after completing therapy, and 4 weeks after completing therapy. CONCLUSION: High-dose dexamethasone therapy, a standard treatment for early B-cell acute lymphoblastic leukemia, can cause adrenal insufficiency lasting more than 4 weeks after cessation of treatment. This problem might be avoided by tapering doses of glucocorticoids and providing supplemental glucocorticoids during periods of increased stress.     

Otoacoustic emissions as a screening test for hearing impairment in children recovering from acute bacterial meningitis

OBJECTIVES: To study the efficacy of otoacoustic emissions (OAEs) as a screening test for hearing impairment in children with acute bacterial meningitis. Hearing tests were performed before discharge from the hospital in an attempt to improve coverage and avoid delays in the diagnosis of postmeningitic hearing loss. METHODS: Children with bacterial meningitis were recruited from 21 centers. In the 48 hours before discharge from the hospital, all patients underwent a thorough audiologic assessment consisting of transient evoked OAEs, auditory brainstem responses (ABRs), otoscopy, and tympanometry. Hearing loss was defined as ABR threshold >/=30 dB. The results of OAE screening were compared with the gold standard of ABR threshold. RESULTS: Of 124 children recruited, we were able to perform both OAEs and ABRs on 110 children. Seven (6.3%) of the 110 children had ABR threshold >/=30 dB; 2 had sensorineural hearing loss and 5 had conductive hearing loss. At follow-up, hearing loss persisted in both cases of sensorineural hearing loss and no new cases were identified. All 7 children with hearing loss failed the OAE screening test. Ninety-four children with normal hearing thresholds passed the test, and 9 failed. Thus, the screening test had a sensitivity of 1.00 (95% confidence interval, 0.59 to 1.00), a specificity of 0.91 (0.85 to 0.97), a positive predictive value of 0. 44 (0.20 to 0.70), and a negative predictive value of 1.00 (0.96 to 1.00). CONCLUSIONS: OAE screening in children recovering from meningitis was found to be feasible and effective. The test was highly sensitive and reasonably specific. Inpatient OAE screening should allow early diagnosis of postmeningitic hearing loss and prompt auditory rehabilitation.     

Risk of hearing impairment in pediatric liver transplant recipients: a single center study

As survival rates following liver transplantation have increased, health care providers must assess the impact of transplantation on dimensions other than traditional medical measures. Hearing impairment may adversely impact social, emotional, cognitive, academic, and speech and language development. We hypothesized that children who undergo liver transplantation are at risk for hearing impairment due to exposure to ototoxic drugs. We conducted a review of 74 children who had undergone liver transplantation between December 1996 and September 2000 at Cincinnati Children's Hospital Medical Center. Hearing was assessed at discharge by an audiologist using age and developmentally appropriate techniques. The principal outcome measure was sensorineural hearing impairment. Independent variables were age at transplantation, United Network for Organ Sharing (UNOS) status at transplantation, primary diagnosis, post-transplant length of hospital stay, days of treatment with aminoglycosides, and days of treatment with loop diuretics. Eleven of 74 children (15%) had sensorineural hearing loss, of whom four had severe to profound hearing loss. Multivariate analyses showed that the adjusted relative risk for hearing loss in patients with hepatoblastoma was 66 and that there was a 5% increase risk for hearing loss for each additional day of hospitalization. Age at transplantation, UNOS status, and days of treatment with loop diuretics or aminoglycosides did not achieve significance in the model. Sensorineural hearing impairment occurs in a subset of pediatric patients following liver transplantation. Patients with hepatoblastoma or those who experience prolonged hospitalization after transplantation are at increased risk. Our observations are of particular importance for pediatric liver transplant recipients since the median age at transplantation is 12-18 months, a critical period for language acquisition.     

Defective leukocyte fungicidal activity in end-organ resistance to 1,25-dihydroxyvitamin D

Recent studies have shown 1,25(OH)2D3 receptor-mediated modulation of leukocyte proliferation, differentiation, and function. We examined the phagocytosis and killing of microorganisms by neutrophils and monocytes from five patients of three families with hereditary resistance to 1,25(OH)2D3. Phagocytosis of microorganisms by patients' neutrophils and monocytes was normal. However, defective neutrophil killing activity toward Candida albicans (30-40% of controls) was found in all patients. The killing of Staphylococcus aureus was normal. The neutrophil chemiluminescence, nitroblue tetrazolium (NBT) dye reduction, and the generation of superoxide ions and hydrogen peroxide by neutrophils and monocytes after induction by either soluble stimuli or zymozan particles, did not differ from those in controls. The neutrophil myeloperoxidase activity was also normal. Monocytes obtained from two patients of different families before long-term calcium infusion therapy and after they became normocalcemic, demonstrated a similar impaired fungicidal activity toward Saccharomyces cerevisiae, indicating that hypocalcemia itself was not the cause of the killing defect. However, the addition of the Ca+2 ionophore A23187 (1 microM) to the test medium restored the monocyte fungicidal activity to normal. As patients' neutrophil cytosolic free calcium concentration was similar to that in controls, it is suggested that 1,25-(OH)2D3 exerts its effect on leukocyte function by a putative receptor-mediated regulation of subcellular calcium localization which may be important for fungicidal activity.     

Nutritional assessment of peripheral blood stem cell transplantation in children

Peripheral blood stem cell transplantation (PBSCT) has many advantages for patients because hematopoiesis and general condition return to normal more rapidly than they do following bone marrow transplantation. Thus, the authors hypothesize that the nutritional condition of patients also returns to normal more rapidly after PBSCT. The duration of insufficient nutrition was investigated in children undergoing PBSCT. The subjects of this study were 8 patients with malignant diseases. The factors measured were body weight, body fat, cholesterol, albumin, pre-albumin, and retinol-binding protein. These parameters were measured a day before transplantation, and then once a week for 4 weeks after transplantation. All parameters were recovered until day 28 from the lowest level in transplantation. In this study, all parameters returned to normal comparatively early. PBSCT causes little damage to patients' nutrition.     

NUTRITIONAL ASSESSMENT OF PERIPHERAL BLOOD STEM CELL TRANSPLANTATION IN CHILDREN

Peripheral blood stem cell transplantation (PBSCT) has many advantages for patients because hematopoiesis and general condition return to normal more rapidly than they do following bone marrow transplantation. Thus, the authors hypothesize that the nutritional condition of patients also returns to normal more rapidly after PBSCT. The duration of insufficient nutrition was investigated in children undergoing PBSCT. The subjects of this study were 8 patients with malignant diseases. The factors measured were body weight, body fat, cholesterol, albumin, pre-albumin, and retinol-binding protein. These parameters were measured a day before transplantation, and then once a week for 4 weeks after transplantation. All parameters were recovered until day 28 from the lowest level in transplantation. In this study, all parameters returned to normal comparatively early. PBSCT causes little damage to patients' nutrition.     

The newborn with hearing loss: detection in the nursery

BACKGROUND: Early detection of hearing loss coupled with appropriate early intervention is critical to speech, language, and cognitive development. These competencies serve as the foundation for later academic skills. For these reasons, many states are undertaking aggressive efforts to screen all newborns before hospital discharge. Universal detection of hearing loss in newborns is a three-stage process composed of 1) the birth admission screen, 2) follow-up and diagnosis, and 3) intervention services. Breakdown at any stage jeopardizes the entire effort. The goals of this research are to examine the birth admission screen by reviewing outcome measurements for 54 228 Texas newborns and to evaluate factors that impact outcomes positively or negatively. METHODOLOGY: All newborns were screened for hearing loss using a physiologic test of auditory function; either screening auditory brainstem responses or transient evoked otoacoustic emissions. Screening occurred in the newborn and intensive care nurseries, before hospital discharge in 9 sites as part of the nursery protocol. Patients. A total of 54 228 newborns were available for screening. OUTCOME MEASURES: Four measures were evaluated and are reported: the number of births screened, the number of newborns who passed the screen before discharge, the number of infants who returned for follow-up, and the number of infants identified with hearing loss. A Birth Screening Performance Index is also calculated. RESULTS: Results are reported for calendar years 1994, 1995, 1996, and through June 1997. A total of 54 228 newborns were available for screening; 52 508 were screened before hospital discharge during their birth admission and 50 721 passed this screen. Infants returning for follow-up screen as outpatients numbered 1224. Over this 31/2-year span, 113 infants who failed the birth admission screening had hearing loss that was sensorineural in nature. From these data, the estimated incidence of hearing loss is 3.14/1000 infants. CONCLUSIONS: Screening in the nursery with low false-positive rates can be achieved when three elements are present: audiology involvement, hospital support, and automated data and information management. Follow-up measures need improvement. Better tracking methods may help assure that at-risk newborns are connected to services.     

Hearing screening of high-risk newborns with brainstem auditory evoked potentials: a follow-up study

Numerous techniques have been used in attempts to find a reliable and efficient screening method for determining auditory function in the newborn. The brainstem auditory evoked potential (BAEP) is the latest method advocated for that purpose. The BAEP was evaluated as a hearing screening test in 168 high-risk newborns between 35 and 45 weeks of conceptual age. Follow-up data were obtained after 1 year (mean 17.3 months) on 134 of the infants (80%). Normal hearing was defined as a reproducible response in both ears to a 25 dB normal hearing level (nHL) click stimulus; 21 infants (12.5%) failed the initial screening test. Follow-up on 19/21 infants revealed 18 infants with normal hearing and one infant with an 80 dB nHL bilateral hearing loss substantiated. One infant with an abnormal screening test died before retesting, and the other infant was lost to follow-up but had only a unilaterally abnormal BAEP. None of the infants with a normal BAEP screening study had evidence of hearing loss on retesting. Sensitivity of the BAEP was 100%, specificity was 86%, predictive value of a positive test was 5.26%, and the predictive value of a negative test was 100%. The incidence of significant hearing loss in our population was between 0.75% (1/134 infants) confirmed, and 2.24% (3/134 infants) including infants who failed screening but were lost to follow-up. The BAEP is a sensitive procedure for the early identification of hearing-impaired newborns. However, the yield of significant hearing abnormalities was less than predicted in other studies using BAEP for newborn hearing screening.     

Alpha-mannosidosis in the guinea pig: a new animal model for lysosomal storage disorders.

Alpha-mannosidosis is a lysosomal storage disorder resulting from deficient activity of lysosomal alpha-mannosidase. It has been described previously in humans, cattle, and cats, and is characterized in all of these species principally by neuronal storage leading to progressive mental deterioration. Two guinea pigs with stunted growth, progressive mental dullness, behavioral abnormalities, and abnormal posture and gait, showed a deficiency of acidic alpha-mannosidase activity in leukocytes, plasma, fibroblasts, and whole liver extracts. Fractionation of liver demonstrated a deficiency of lysosomal (acidic) alpha-mannosidase activity. Thin layer chromatography of urine and tissue extracts confirmed the diagnosis by demonstrating a pattern of excreted and stored oligosaccharides almost identical to that of urine from a human alpha-mannosidosis patient. Widespread neuronal vacuolation was observed throughout the CNS, including the cerebral cortex, hippocampus, thalamus, cerebellum, midbrain, pons, medulla, and the dorsal and ventral horns of the spinal cord. Lysosomal vacuolation also occurred in many other visceral tissues and was particularly severe in pancreas, thyroid, epididymis, and peripheral ganglion. Axonal spheroids were observed in some brain regions, but gliosis and demyelination were not observed. Ultrastructurally, most vacuoles in both the CNS and visceral tissues were lucent or contained fine fibrillar or flocculent material. Rare large neurons in the cerebral cortex contained fine membranous structures. Skeletal abnormalities were very mild. Alpha-mannosidosis in the guinea pig closely resembles the human disease and will provide a convenient model for investigation of new therapeutic strategies for neuronal storage diseases, such as enzyme replacement and gene replacement therapies.     

Implementation and results of bedside hearing screening with automated auditory brainstem response in the neonatal intensive care unit

Aim: To evaluate implementation and results of neonatal hearing screening with automated auditory brainstem response (AABR) by bedside nurses in a single‐centre neonatal intensive care unit (NICU). Methods: Retrospective review of charts of 2074 newborns admitted over a 4‐year period. Results: One thousand eight hundred and 24 newborns (88%) were screened. A ‘pass’ result was obtained in 1761 patients (96.5%). From 63 infants with ‘refer’, 40 were tested with auditory brainstem response: in 28 hearing loss was confirmed. Three hundred and nine neonates were screened before postmenstrual age (PMA) of 34 weeks: 78% successfully passed the first test. Sixty‐seven infants with ‘refer’ at the first test before PMA of 34 weeks were re‐evaluated: 48 had normal hearing tests, 24 of whom still younger than 34 weeks. For 12 of 19 infants with ‘refer’ before 34 weeks, follow‐up was available: in 7 hearing loss was confirmed. Conclusion: Neonatal hearing screening with AABR can be easily performed by the bedside nurse in the NICU even in premature babies before 34 weeks PMA. A ‘pass’ result can be obtained in almost 80% of them; a ‘refer’ result at that age, however, must be interpreted cautiously, as false ‘refer’ occurred in 5/12 of these infants.     

Improvement of growth after growth hormone treatment in children who undergo liver transplantation

BACKGROUND: Chronic liver insufficiency in children is frequently associated with growth retardation. Growth resumes after successful orthotopic liver transplantation in the majority of children with previous chronic liver failure. However, a subgroup of children demonstrates stunted growth even after orthotopic liver transplantation. The current study was conducted to determine whether administration of recombinant human growth hormone might benefit these patients. METHODS: Ten children were identified who met the criteria of growth failure despite normal transplant function in a cohort of 60 transplantation patients: height standard deviation score (hSDS) for chronological age less than -2, and growth velocity SDS (gvSDS) for chronological age equaling 0. Seven of these patients were treated with subcutaneous injections of recombinant human growth hormone at 4.0 U/m2 body surface area per day for at least 1 year. Two patients in this group showed insufficient growth hormone response to stimulation (arginine, clonidine) before therapy. Treatment was begun after a median time of 4.6 years after liver transplantation (2.55-8.4 years). Five children were treated with cyclosporin A and prednisolone and two with tacrolimus and prednisolone for maintenance immunosuppression. RESULTS: Within 3 months of treatment, median serum levels of insulin-like growth factor (IGF)-I increased from 0.05 to 0.71 (P < 0.02). Within 1 year, median hSDS improved from -2.7 (range, -5.6 to -2.3) to -2.1 (-4.5 to -1.4; P < 0.03). Median annual growth rate increased from 3.9 cm/year (range, 3-6) in the year before treatment to 8.2 cm/year (range, 6.1-10.4; P < 0.02) after the beginning of recombinant human growth hormone therapy. All patients tolerated treatment without side effects. During the cumulative treatment time of 14 years no rejection episode was observed. CONCLUSIONS: Short-statured prepubertal liver transplant recipients who do not show sufficient compensatory growth after transplantation benefit from treatment with recombinant human growth hormone. Treatment with the hormone was safe without any side effects.     

Auditory and vestibular findings in Fabry disease: a study of hemizygous males and heterozygous females

AIM: This study aimed to evaluate audiological and vestibular involvement in Fabry disease and the early effects of enzyme replacement therapy with human alpha-galactosidase A. METHODS: Fourteen patients (10 males, 4 females) aged 14-57 years were studied. Each patient underwent a clinical (history of otological and vestibular aspects, otoscopy) and instrumental (pure tone and speech audiometry, impedance, auditory brainstem response and oto-acoustic emission recordings, vestibular caloric tests, electronystagmography during acceleratory stimulation, dynamic posturography) evaluation before starting enzyme replacement therapy. RESULTS: Fifty per cent of patients complained of hearing symptoms (hearing loss, tinnitus, ear fullness). Subjective hearing loss was present in six cases and in three cases it was the first reported symptom of Fabry disease. In six of the seven cases the onset and/or progression of hearing symptoms were sudden. Vertigo or dizziness was reported by four patients and in two cases was associated with hearing symptoms. Audiological evaluation showed sensorineural hearing loss in eight patients (5 males, 3 females). Hearing loss was unilateral in six cases and bilateral in the remaining two cases. The hearing loss (HL) ranged from 30 to 80 dB HL (mean, 43 dB HL) and the lesion was always cochlear. Vestibular examination showed abnormalities in four patients (bilateral weak/abolished response in three cases, side prevalence in one case), which were not related to either the audiological results or the history of vertigo/dizziness. CONCLUSION: Involvement of the inner ear is common in men and women with Fabry disease. We found a high incidence of cochlear hearing loss, which was typically unilateral and showed onset and/or progression by sudden episodes. Vascular or hydropic mechanisms could be hypothesized to explain audiological findings. Vestibular involvement had a lower incidence and showed a different pattern, thus suggesting that several pathophysiological mechanisms could play a role in determining inner ear damage in Fabry disease. Our preliminary results show that enzyme replacement therapy may stabilize hearing function; however, further follow-up is required.