PURPOSE:To determine early signs of disease in patients with childhood-onset cerebral adrenoleukodystrophy (COCALD) with the use of proton MR spectroscopy.METHODS:Eleven children with posterior COCALD involvement and three children with anterior COCALD involvement were studied with single-voxel proton MR spectroscopy and neuropsychological testing. Findings were compared with those in five healthy control subjects.RESULTS:Areas of abnormal T2 signal intensity in children with COCALD showed abnormal metabolite ratios relative to those of control subjects as follows: decreased N-acetylaspartate (NAA)/Creatine (Cr) and NAA/Choline (Ch) and increased Ch/Cr. Metabolite ratios from normal-appearing brain regions in the same patients also were abnormal, with reduced NAA/Cr and NAA/Ch and increased Ch/Cr values. The mean metabolite ratios in normal-appearing regions were between those in the abnormal regions and those found in the control subjects. Statistical comparison of these ratios with neuropsychological test scores, which are specific for anterior and posterior brain functions, showed a significant correlation with the abnormal metabolite ratios. Our results indicate that the normal-appearing brain regions in these patients are metabolically abnormal.CONCLUSION:Proton MR spectroscopy could be a useful noninvasive tool to evaluate extent of disease in patients with COCALD.

Adrenoleukodystrophy (ALD) is an X-linked disorder whose gene and peroxisomal transport membrane product have been identified. The result of the deficiency of the protein membrane product is accumulation of very-long-chain fatty acids (VLCFA) in plasma, brain, and adrenal glands. Because ALD is an X-linked disorder and is easily biochemically characterized by elevations in VLCFA, boys can be readily identified prior to the onset of symptoms.(1) Phenotypic variability is characteristic of ALD and even within affected family members, age of onset is highly variable.(2) Forms include symptom free, Addison's disease, late onset adrenomyeloneuropathy (AMN), and childhood onset cerebral ALD, a rapidly progressive and fatal disease.(2-4)Depending on ascertainment method, estimates range from 25 to 50% of patients will develop the cerebral form.(2,5) Cerebral ALD occurs in the primarily in the first decade with a peak onset at 7 years,(2) although onset of cerebral disease can occur even in adults. Generally the younger the age of onset, the faster the rate of neuropsychological and neurological decline.(6)ALD is challenging due to lack of phenotypic concordance and inability to predict who will develop the cerebral disease. No current method permits identification of which children in the presymptomatic state will develop cerebral ALD.(7) While the biochemical abnormality signals the abnormal genotype, detecting the early signs of cerebral disease relies on longitudinal synthesis of neuropsychological, neurologic, and imaging data.Studies have indicated that Lorenzo's oil and dietary restriction do not prevent the onset of cerebral disease(8,9) Whether these interventions alter the age of onset or the rate of progression is not yet known. Bone marrow transplant offers a hope of arresting the course of the disease. Aubourg reported the first successful BMT for ALD.(10) His case demonstrated recovery in intellectual function and loss of MRI abnormality. Altogether 65 patients have been transplanted throughout the world. In the U.S. and Canada as of July 1996, of 34 patients transplanted, 23 surviving patients have provided favorable outcome data. Continued engraftment is reflected in 100% donor peripheral white cell DNA in the recipient. However, BMT has been found to be effective only in the early stages of the cerebral disease.(11) The short-term outcomes of BMT for patients with early disease indicate stability of mental ability for all surviving patients.(6,12) Our data suggests that early identification of the onset of the disease process is necessary so that BMT can occur before the patient has significant progression of disease.A set of guidelines(6) have been developed for eligibility for BMT that includes 1) MRI abnormality on the Lees scale,(13) 2) functional and cognitive deterioration over time, and 3) evidence of moderately preserved CNS residual function as indicated on neuropsychological testing and MRI.We present three studies, two investigating the sensitivity of measures to detect clinical deterioration and response to BMT, and the third, preliminary results of five-year outcome of boys transplanted for ALD at Minnesota.

Long-term survival and improved neuropsychological function have occurred in selected children with Hurler syndrome (MPS I H) after successful engraftment with genotypically matched sibling bone marrow transplantation (BMT). However, because few children have HLA-identical siblings, the feasibility of unrelated donor (URD) BMT as a vehicle for adoptive enzyme therapy was evaluated in this retrospective study. Forty consecutive children (median, 1.7 years; range, 0.9 to 3.2 years) with MPS I H received high-dose chemotherapy with or without radiation followed by BMT between January 27, 1989 and May 13, 1994. Twenty-five of the 40 patients initially engrafted. An estimated 49% of patients are alive at 2 years, 63% alloengrafted and 37% autoengrafted. The probability of grade II to IV acute graft-versus-host disease (GVHD) was 30%, and the probability of extensive chronic GVHD was 18%. Eleven patients received a second URD BMT because of graft rejection or failure. Of the 20 survivors, 13 children have complete donor engraftment, two children have mixed chimeric grafts, and five children have autologous marrow recovery. The BM cell dose was correlated with both donor engraftment and survival. Thirteen of 27 evaluable patients were engrafted at 1 year following URD BMT. Neither T-lymphocyte depletion (TLD) of the bone marrow nor irradiation appeared to influence the likelihood of engraftment. Ten of 16 patients alive at 1 year who received a BM cell dose greater than or equal to 3.5 x 10(8) cells/kg engrafted, and 62% are estimated to be alive at 3 years. In contrast, only 3 of 11 patients receiving less than 3.5 x 10(8) cells/kg engrafted, and 24% are estimated to be alive at 3 years (P = .05). The mental developmental index (MDI) was assessed before BMT. Both baseline and post-BMT neuropsychological data were available for 11 engrafted survivors. Eight children with a baseline MDI greater than 70 have undergone URD BMT (median age, 1.5 years; range, 1.0 to 2.4 years). Of these, two children have had BMT too recently for developmental follow-up. Of the remaining six, none has shown any decline in age equivalent scores. Four children are acquiring skills at a pace equal to or slightly below their same age peers; two children have shown a plateau in learning or extreme slowing in their learning process. For children with a baseline MDI less than 70 (median age, 2.5 years; range, 0.9 to 2.9 years), post-BMT follow-up indicated that two children have shown deterioration in their developmental skills. The remaining three children are maintaining their skills and are adding to them at a highly variable rate. We conclude that MPS I H patients with a baseline MDI greater than 70 who are engrafted survivors following URD BMT can achieve a favorable long-term outcome and improved cognitive function. Future protocols must address the high risk of graft rejection or failure and the impact of GVHD in this patient population.

PURPOSE: To determine the potential of proton MR spectroscopy to monitor patients with childhood-onset cerebral adrenoleukodystrophy (COCALD). METHODS: Single-voxel MR spectroscopy was performed in 16 children with COCALD (24 examinations) who had had no treatment and in 7 children (13 examinations) who had had bone marrow transplantation. RESULTS: In the untreated children with clinically active COCALD, the metabolite ratios N-acetyl-aspartate (NAA)/creatine (Cr) and NAA/choline (Ch) were decreased while Ch/Cr was increased. This trend agrees well with those reported by other researchers, although different experimental sequences and parameters were used in our study. Comparison of these ratios with those from a control group yielded significant differences in the occipital region. In the children who were clinically stable after bone marrow transplantation, the mean levels of the three ratios were between those of the control subjects and the patients with untreated COCALD: the differences in these ratios approached significance. In patients who had been monitored periodically, MR spectroscopy metabolite ratios correlated well with the dementia rating score, reflecting clinical status. CONCLUSION: There is good correlation between MR spectroscopy metabolite ratios and a patient's clinical status. MR spectroscopy appears to be a useful, noninvasive tool to monitor patients with adrenoleukodystrophy, and it increases the overall sensitivity of MR techniques in clinical applications.

Neuropsychological assessment is essential in providing documentation of the untreated natural history of storage diseases associated with dementia and quantifying the effectiveness of treatment on central nervous system function. Baseline characterization and outcome of bone marrow transplantation (BMT) for three leukodystrophies and three mucopolysaccharidoses are presented. Results suggests that BMT for Hurler syndrome, adrenoleukodystrophy, and globoid cell leukodystrophy can be effective in preventing dementia if done early enough in the disease. Sanfilippo and Hunter syndromes do not benefit and BMT is not recommended. For metachromatic leukodystrophy, BMT is not recommended for symptomatic early-onset forms of the disease. Further longitudinal follow-up is needed to determine whether the benefits outweigh the risks of BMT for late-onset and preclinical metachromatic leukodystrophy.