Pelizaeus-Merzbacher Disease (PMD) is a rare X-linked recessive leukodystrophy caused by mutations in the proteolipid protein 1 gene on the Xq22 chromosome. PMD is a dysmyelinating disorder characterized by variable clinical presentation and course. Symptoms range from mild motor deficits to progressive spasticity and neurologic decline resulting in death at an early age. There is no definitive curative treatment. This report presents the clinical course of 2 young boys with PMD who are the first known patients to receive umbilical cord blood transplantation as a therapeutic intervention to stabilize disease progression. Pretransplantation evaluation revealed that both patients had significant motor deficits as well as delayed cognitive function as compared with age-matched peers. Brain imaging revealed varying degrees of hypomyelination. Both patients received myeloablative chemotherapy followed by an unrelated donor umbilical cord blood infusion, which they tolerated well with no major transplantation-related complications. At 7-years and 1-year posttransplantation, respectively, both boys are making slow neurocognitive improvements and show no evidence of functional decline. Imaging results show stable or improving myelination. Although the results of unrelated donor umbilical cord blood transplantation in these 2 boys with PMD are encouraging, longer-term follow-up will be necessary to assess the effect of this treatment on the variable natural disease course.
- Pelizaeus-Merzbacher disease
- umbilical cord blood transplantation
- hematopoietic stem cell transplantation
- developmental delay
- CNS —
- central nervous system
- DUMC —
- Duke University Medical Center
- GvHD —
- graft-versus-host disease
- PLP1 —
- proteolipid protein 1 (gene)
- PMD —
- Pelizaeus-Merzbacher disease
- PNS —
- peripheral nervous system
- UCBT —
- umbilical cord blood transplantation
Pelizaeus-Merzbacher disease (PMD) is a rare, progressive leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene leading to dysmyelination in the central and peripheral nervous systems (CNS and PNS, respectively). Severe disease is associated with death in the first decade of life, whereas milder forms show slower progression. No formal natural history studies have been conducted to date, and no effective curative treatment has been described.
Umbilical cord blood transplantation (UCBT) has been successfully used to treat certain life-threatening inherited metabolic diseases, mostly lysosomal and peroxisomal storage disorders.1 Disease stabilization may be mediated through engrafting donor cells that become a source of enzyme replacement therapy. When performed early in the disease process, UCBT can stabilize disease progression. This effect has been observed in selected diseases (eg, adrenoleukodystrophy) in which enzyme replacement is not the mechanism through which UCBT favorably alters the natural history of the disease.2–5 Although the mechanisms underlying the benefit of UCBT in these diseases is not fully understood, we hypothesized that disease stabilization occurs through engraftment of donor cells in the brain, benefitting children with other types of demyelinating diseases. In this report, we describe the first 2 patients treated with UCBT for PMD.
Families were self-referred to Duke University Medical Center (DUMC), and parents provided written informed consent before treatment. Patient 1 was enrolled in an Investigational New Drug-sponsored clinical trial, testing whether engraftment could be accelerated by infusion of aldehyde dehydrogenase cells primed with hematopoietic cytokines before transplantation.6 Both patients were enrolled in the Center for International Blood and Marrow Transplant Research outcomes database, the federally mandated research database created as part of the C.W. Bill Young Cell Transplantation Program.7 The DUMC Institutional Review Board approved both studies. Patient 1 was included in a previous report.1
Patients underwent molecular diagnostic testing to confirm PMD diagnosis and to determine PLP1 mutation (Table 1).
Neurophysiologic and Neurodevelopmental Evaluation
Neurophysiologic studies and imaging evaluated CNS and PNS function pre- and posttransplantation. Standardized neurodevelopmental tools were used to assess neurocognitive and developmental milestones pre- and posttransplantation (Tables 2 and 3).
Transplant Evaluation and Procedure
Diagnostic testing assessed major organ function pre- and posttransplantation as previously described.1 Patients received myeloablative transplant conditioning with busulfan, cyclophosphamide, and antithymocyte globulin.1 One day after completing chemotherapy, they received an infusion of a 5/6 HLA antigen–matched, unrelated umbilical cord blood unit, thawed and washed in dextran/albumin before infusion.8 Graft-versus-host disease (GvHD) prophylaxis and supportive care measures were followed as previously described.1,2
Patient 1 is a multiracial male born at term after an uncomplicated pregnancy. He is an only child with no significant family history. Shortly after birth, he developed mild arm tremors, which could be extinguished when held. At 1 month of age, he had head bobbing; bilateral, high-frequency, pendular horizontal nystagmus; choreiform movements; and a brisk startle response. At 3 months of age he had an abnormal EEG with fast rhythmic activity in the central region and parietal/temporal sharp waves during sleep; an MRI at 7 months of age revealed findings indicative of poor myelination for age (Fig 1). Testing confirmed the PMD diagnosis (Table 1). Because of progressive symptoms his parents requested a consultation for UCBT. The team at DUMC evaluated him at 8 months of age and agreed to perform the procedure. After myeloablative chemotherapy, he underwent UCBT at 9 months of age (Table 4). He engrafted on day +17 after cord blood infusion. He subsequently developed grade 2 acute skin GvHD followed by mild chronic skin GvHD. He developed autoimmune hemolytic anemia and thrombocytopenia at 7 months posttransplantation, which was treated with corticosteroids, rituximab, and azathioprine. He had a gastrostomy tube placed 1 year posttransplantation; it was removed 9 months later because oral intake had improved. Adrenal insufficiency, due to long-term corticosteroid use, was treated with physiologic hydrocortisone replacement until 2.5 years posttransplantation. His chronic medical issues currently include gastroesophageal reflux, recurrent otitis media with myringotomy tube placement, cholelithiasis, and nearsightedness. He is currently 7 years posttransplantation, durably engrafted with >98% donor cells, and has discontinued immunosuppressive medications with normal immune reconstitution.
Patient 2 is a white male born at term by cesarean delivery with a nuchal cord at delivery. At 4 months old, he had rotary and pendular, disconjugate nystagmus, with amblyopia. At 6.5 to 7.5 months old he was found to be hypotonic with gross motor deficits. An MRI at 9 months old was reportedly normal, but delayed myelination was noted retrospectively. At 16 months old he had intermittent nystagmus, bilateral facial weakness, truncal hypotonia, upper extremity weakness, and hypertonia with dystonic posturing in his extremities. Genetic testing confirmed PMD (Table 1). His parents requested consultation for UCBT at DUMC, and his transplantation was performed after myeloablative conditioning at the age of 29 months (Table 4). He engrafted on day +23 after cord blood infusion. He subsequently experienced mild, grade 1 acute skin GvHD. He required physiologic hydrocortisone replacement until 1 year posttransplantation. At 14 months posttransplantation, he remains durably engrafted with >98% donor cells and has discontinued immunosuppression, with normal immune function.
Neurocognitive and Motor Function Outcomes
Both patients showed significant gains posttransplantation in cognitive function, although motor function has lagged behind (Table 3). Head circumference in both boys remained normal for age. At the time of last follow-up at 7 years of age, patient 1 showed delayed development, with fine motor skills equivalent to those of a 15-month-old. His level of independence (based on a parental evaluation using the Scales of Independent Behavior–Revised Full-Scale Form) was equivalent to that of a 21-month-old, whereas his visual reception was equivalent to that of a 46-month-old. Gross motor skill age equivalents based on the Peabody Developmental Motor Skills–Second Edition scale included the following: reflexes, 5 months; stationary, 11 months; locomotion, 9 months; and object manipulation, 13 months. Neurologic examination revealed cerebellar ataxia and tremor, choreoathetosis, proximal extremity weakness, and dystonic posturing. He attends third grade, mainstreamed in a typical class with special education support.
At 1-year posttransplantation, patient 2 uses a stander and a reverse walker and wears lower extremity braces. He has excellent upper extremity function. Testing at 41 months of age revealed cognitive function at an approximate age equivalence of a 30-month-old, but substantial delay in motor function (estimated age equivalence of a 9- to 11-month-old). He receives Early Intervention services including speech, occupational, and physical therapy.
Both patients displayed decreased myelination, measured by fractional anisotropy on diffusion tensor imaging, on pretransplantation MRI evaluation, with altered signal intensity within the brainstem and deep white matter (Table 5). In patient 1, imaging at age 7 months showed abnormal myelination for age (Fig 1). On posttransplantation imaging at 19 months of age, myelination had improved. MRI at age 69 months showed stable myelination compared with the previous posttransplantation imaging.
Diagnostic imaging of patient 2 at 9 months of age showed a moderate decrease in myelination for age (Fig 2). He showed interval myelination between his 9-month MRI and his pretransplantation MRI at 25 months old. On his posttransplantation images at age 42 months, his MRI revealed an interval increase in myelination.
In this report, we describe the clinical outcomes after UCBT of 2 young boys with severe phenotype PMD. Both patients tolerated the procedure well without major posttransplantation complications and remain durably engrafted with donor cells. Both continue to gain cognitive skills, but remain impaired compared with age-matched peers. Brain MRI revealed sustained interval improvement in myelination posttransplantation, although overall myelination remained less than expected for chronological age. Motor function improved to a greater extent in patient 2 as compared with patient 1. This finding may be due, in part, to the fact that patient 1 had a more severe disease presentation with extensive involuntary movements further impairing motor function.
PMD is a leukodystrophy usually inherited in an X-linked recessive pattern with an estimated prevalence of 1 in 200 000 to 500 000 live male births. The natural history is highly variable, and there is no known curative treatment of PMD.9 Gupta et al10 recently published the results of a phase 1 study investigating the safety and efficacy of intracranial injections of fetus-derived neural stem cells in 4 young boys with PMD. They showed a favorable safety profile and suggested that cell engraftment and donor-derived myelination occurred in the transplanted host white matter. UCBT after myeloablative chemotherapy has been used to treat > 500 children with inherited metabolic diseases around the world in the last decade. In general, in children with early-stage disease, the procedure is well tolerated and overall survival ranges between 80% and 90%. Donor stem cell engraftment is durable, and in diseases with enzyme deficiencies, enzyme levels normalize in the blood. Favorable effects on clinical disease have been seen in patients with mucopolysaccharidosis 1, adrenoleukodystrophy, juvenile metachromatic leukodystrophy, and selected patients with Krabbe disease.1–5
In connatal PMD, the most severe form of the disease, infants present in the perinatal period with nystagmus, stridor, and hypotonia, and die in the first decade of life. Other manifestations include the following: nonepileptic seizures, microcephaly, weak cry, difficulty sucking, titubation, and poor muscle reflexes.11 Classic PMD presents with nystagmus at 2 to 6 months of age. Later in childhood, delays in motor and speech development, ataxia, and hypotonia are observed. Children slowly deteriorate over the first few decades of life and die as young adults.
The PLP1 gene normally undergoes alternative splicing to produce 2 proteins, PLP1 and DM20, which stabilize and maintain the myelin sheath along CNS and PNS axons. They also play a role in proper development of oligodendrocyte precursors.11 Duplications of the PLP1 gene, as seen in patient 1 in this report, are present in 50% to 75% of patients with PMD and are associated with the most severe forms of clinical disease. Increased PLP1 gene expression portends a worse clinical outcome; the greater number of gene copies, the more severe the phenotype.12 Point mutations in the PLP1 gene account for 15% to 20% of PMD cases and result in production of a prematurely terminated protein, which is toxic to the oligodendrocyte, causing dysmyelination.13 Splicing mutations alter relative expression of PLP1 and DM20 protein and lead to variable phenotypes.14 Patient 2 in our study has a mutation in exon 6, yielding a splicing variant, and has a less severe phenotype than patient 1. Null mutations may lead to an even milder clinical phenotype with moderate spastic quadriparesis, mild cognitive delay, ataxia, and peripheral neuropathy.14
PMD is associated with dysmyelination and cortical atrophy on MRI.15 White matter atrophy has been reported on postmortem brain examination.16 Both of our patients showed improvement or stabilization of myelination posttransplantation at 7-years and 1-year, respectively, albeit not at the rate seen in a normal child. Natural history studies of radiographic changes in patients with PMD are lacking. However, one would expect disease progression to be associated with slow loss of myelin and subsequent white matter atrophy; hence, the absence of these findings suggests a beneficial effect, stopping or slowing disease progression after UCBT.
We report the results of UCBT in 2 boys with moderate-to-severe PMD. Both boys tolerated transplantation well, including exposure to myeloablative chemotherapy. With 7-year and 1-year follow-up, they showed stabilization of disease with significant gains in cognitive skills and modest gains in motor development. MRI results suggest interval myelination, which is encouraging. Longer-term follow-up is needed to fully assess the effects of UCBT on the course of PMD in these 2 patients. The interpretation of our results is complicated by the lack of formal natural history studies and variability of the clinical course in this rare disease. We will continue to follow our patients to confirm these preliminary observations.
- Accepted April 1, 2014.
- Address correspondence to Jessica Wishnew, MD, Duke University Medical Center, Box 3850, 2400 Pratt St, Durham, NC 27710. E-mail:
Dr Wishnew reviewed the patient information, drafted the initial manuscript, and constructed the tables and figures; Dr Page conceptualized the manuscript content and reviewed and revised the manuscript; Ms Wood gathered patient data and recorded patient data in the medical record; Dr Galvin assisted with the review and interpretation of the patients’ MRI scans and helped construct the MRI portion of the manuscript and figures; Dr Provenzale selected the patients’ MRI scans for review, assisted in the interpretation of the MRI scans, and reviewed the MRI portion of the manuscript and figures; Dr Escolar gathered patient data, recorded patient data in the medical record, and reviewed and revised the manuscript; Dr Gustafson gathered patient data and recorded patient data in the medical record; Dr Kurtzberg conceptualized the manuscript content and edited and critically reviewed the manuscript; and all authors approved the final manuscript as submitted.
FINANCIAL DISCLOSURE: Dr Kurtzberg is the medical director of the CORD:USE Cord Blood Bank and the director of the Carolinas Cord Blood Bank. She holds a consultancy position as the National Marrow Donor Program Medical Advisor Co-Chair, part of the Cord Blood Working Group and has a grant through the Health Resources and Services Administration Cord Blood Public Banking Contract. The other authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
- Prasad VK,
- Mendizabal A,
- Parikh SH,
- et al
- ↵Kurtzberg J MA, Carter S, Reese M, et al. Augmentation of standard umbilical cord blood transplantation with ALDHbr cells: results of a phase i study in pediatric patients [abstract 64]. Biol Blood Marrow Transplant. 2008:abst. 64, page 41
- ↵US Department of Health and Human Services, Health Resources and Services Administration. HRSA Web site. Available at: www.hrsa.gov/index.html. Website accessed April 2, 2014
- Rubinstein P,
- Dobrila L,
- Rosenfield RE,
- et al
- ↵Gupta N, Henry RG, Strober J, et al. Neural stem cell engraftment and myelination in the human brain. Sci Transl Med. 2012;4(155):155ra137
- Wolf NI,
- Sistermans EA,
- Cundall M,
- et al
- ↵Lassuthova P, Zaliova M, Inoue K, et al. Three new PLP1 splicing mutations demonstrate pathogenic and phenotypic diversity of Pelizaeus-Merzbacher disease. J Child Neurol. Epub 2013
- Cailloux F,
- Gauthier-Barichard F,
- Mimault C,
- et al.,
- Clinical European Network on Brain Dysmyelinating Disease
- Copyright © 2014 by the American Academy of Pediatrics