PLP1 gene duplication as a cause of the classic form of Pelizaeus-Merzbacher disease - case report

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked dysmyelination disorder of the central nervous system (CNS). PMD is caused by mutations in the PLP1 gene located at Xq22 and encoding the major myelin component in CNS, proteolipid protein 1 (PLP1). The disease is clinically heterogeneous. Phenotypes are generally categorized into classic and connatal forms. Connatal PMD has more rapid progression with early death, while patients with classic PMD generally survive to adulthood. Both forms of the disease are caused by point mutations as well as rearrangements - multiplication (mainly duplication) and deletion of the PLP1 gene. We present a case of a male patient affected by the classic form of PMD with benign course, except severe dysarthria with the characteristic laryngeal stridor, which is more typical for connatal form of the disease. The diagnosis has been confirmed at the molecular level. The patient has duplication of all 7 exons of the PLP1 gene. This duplication was inherited from the patient's mother, who is an unaffected carrier of the mutation. The patient's family pedigree analysis revealed the interfamilial variability of the phenotype among affected male relatives.     

Brain N-acetylaspartate is reduced in Parkinson disease with dementia

Persons with Parkinson disease (PD) are at risk of developing dementia. Of the dementias affecting patients with PD, PD with dementia (PDD) is not well understood, although brain imaging studies to date have observed characteristic patterns of brain atrophy. Metabolic differences have been observed in magnetic resonance spectroscopy (MRS) studies comparing patients with PDD to nondemented PD patients, although it is unclear whether PDD patients have abnormally low MRS ratios compared with healthy age-matched adults. In this study, 12 patients with PDD, 12 patients with PD and no dementia, and 12 age-matched healthy older adults underwent MRS of the posterior cingulate gyrus. Patients with PDD showed lower N-acetylaspartate/creatine (NAA/Cr) compared with controls (P=0.004) and compared with nondemented PD patients (P=0.003). No abnormalities were observed in choline/Cr or myo-Inositol/Cr. NAA/Cr was correlated with mental status in patients with PD and in patients with PDD (r=0.56; P=0.029). The findings suggest that reduced NAA/Cr of the posterior cingulate could be used as a marker for dementia in patients with PD. Future studies investigating the utility of brain MRS as a predictor of dementia in PD and comparing brain metabolism in PDD with other dementias seem warranted.     

A novel PLP mutation in a Japanese patient with mild Pelizaeus-Merzbacher disease

Pelizaeus-Merzbacher disease (PMD) is a rare dysmyelinating disorder due to mutations in the proteolipid protein (PLP) gene. PLP gene mutations are responsible for a broad spectrum of disease, from the most severe form, connatal PMD, to a less severe form, spastic paraplegia 2 (SPG2). We describe here a very mild case of PMD in a patient who presented with nystagmus in early infancy and was unable to walk until 1 year 7 months of age. Brain magnetic resonance imaging (MRI) at 1 year 7 months of age revealed white matter abnormalities typical of PMD. Genetic testing revealed a novel mutation of the PLP gene (Gly197Arg). The patient presented with only mildly ataxic gait and slurred speech at the age of 4 years. Gly197Arg is the first novel mutation located within exon 4 of the PLP gene and associated with mild PMD/SPG2 in a Japanese patient.     

Brain ubiquitin is markedly elevated in Alzheimer disease.

Levels of ubiquitin, microtubule associated protein tau and tubulin were determined by immunoassays in homogenates of cerebrum and cerebellum of Alzheimer disease and aged control cases. Ubiquitin levels increased many fold in the cerebral cortex of Alzheimer disease cases and the increase correlated strongly with the degree of neurofibrillary changes in the tissue. The increase in ubiquitin was much less remarkable in the cerebral white matter. Cerebellum which is unaffected with neurofibrillary changes in Alzheimer disease had normal levels of ubiquitin both in gray matter and in white matter. There was an appreciable increase in abnormally phosphorylated tau in an Alzheimer disease brain with severe neurofibrillary degeneration, whereas the normal tau levels were increased only slightly. Tubulin was slightly decreased in the cerebral gray matter but not in the adjacent white matter. Marked increase in brain ubiquitin in Alzheimer disease suggests the role of ubiquitin in the pathobiology of Alzheimer disease.     

PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2

Pelizaeus-Merzbacher disease (PMD) and its allelic disorder, spastic paraplegia type 2 (SPG2), are among the best-characterized dysmyelinating leukodystrophies of the central nervous system (CNS). Both PMD and SPG2 are caused by mutations in the proteolipid protein 1 (PLP1) gene, which encodes a major component of CNS myelin proteins. Distinct types of mutations, including point mutations and genomic duplications and deletions, have been identified as causes of PMD/SPG2 that act through different molecular mechanisms. Studies of various PLP1 mutants in humans and animal models have shed light on the genomic, molecular, and cellular pathogeneses of PMD/SPG2. Recent discoveries include complex mutational mechanisms and associated disease phenotypes, novel cellular pathways that lead to the degeneration of oligodendrocytes, and genomic architectural features that result in unique chromosomal rearrangements. Here, I review the previous and current knowledge of the molecular pathogenesis of PMD/SPG2 and delineate future directions for PMD/SPG2 studies.     

Misalignment of PLP/DM20 transmembrane domains determines protein misfolding in Pelizaeus-Merzbacher disease

A large number of genetic diseases have been associated with truncated or misfolded membrane proteins trapped in the endoplasmic reticulum (ER). In the ER, they activate the unfolded protein response, which can trigger cell death. Hence, a better understanding of protein misfolding features might help in developing novel therapies. Here, we have studied the molecular basis of Pelizaeus-Merzbacher disease, a leukodystrophy defined by mutations of the PLP1 gene and ER retention of two encoded tetraspan myelin proteins, PLP and DM20. In mouse oligodendroglial cells, mutant isoforms of PLP/DM20 with fewer than all four transmembrane (TM) domains are fully ER retained. Surprisingly, a truncated PLP with only two N-terminal TM domains shows normal cell-surface expression when coexpressed with a second truncated PLP harboring the two C-terminal TM domains. This striking ability to properly self-align the TM domains is disease relevant, as shown for the smaller splice isoform DM20. Here, the increased length of TM domain 3 allows for compensation of the effect of several PLP1 point mutations that impose a conformational constraint onto the adjacent extracellular loop region. We conclude that an important determinant in the quality control of polytopic membrane proteins is the free alignment of their TM domains.     

PLP overexpression perturbs myelin protein composition and myelination in a mouse model of Pelizaeus-Merzbacher disease

Duplication of PLP1, an X‐linked gene encoding the major myelin membrane protein of the human CNS, is the most frequent cause of Pelizaeus‐Merzbacher disease (PMD). Transgenic mice with extra copies of the wild type Plp1 gene, a valid model of PMD, also develop a dysmyelinating phenotype dependant on gene dosage. In this study we have examined the effect of increasing Plp1 gene dosage on levels of PLP/DM20 and on other representative myelin proteins. In cultured oligodendrocytes and early myelinating oligodendrocytes in vivo, increased gene dosage leads to elevated levels of PLP/DM20 in the cell body. During myelination, small increases in Plp1 gene dosage (mice hemizygous for the transgene) elevate the level of PLP/DM20 in oligodendrocyte soma but cause only minimal and transient effects on the protein composition and structure of myelin suggesting that cells can regulate the incorporation of proteins into myelin. However, larger increases in dosage (mice homozygous for the transgene) are not well tolerated, leading to hypomyelination and alteration in the cellular distribution of PLP/DM20. A disproportionate amount of PLP/DM20 is retained in the cell soma, probably in autophagic vacuoles and lysosomes whereas the level in myelin is reduced. Increased Plp1 gene dosage affects other myelin proteins, particularly MBP, which is transitorily reduced in hemizygous mice but consistently and markedly lower in homozygotes in both myelin and naïve or early myelinating oligodendrocytes. Whether the reduced MBP is implicated in the pathogenesis of dysmyelination is yet to be established. © 2006 Wiley‐Liss, Inc.     

Processing of PLP in a model of Pelizaeus-Merzbacher disease/SPG2 due to the rumpshaker mutation

The rumpshaker mutation of the X-linked myelin proteolipid protein (PLP1) gene causes spastic paraplegia type 2 or a mild form of Pelizaeus-Merzbacher disease in man. The identical mutation occurs spontaneously in mice. Both human and murine diseases are associated with dysmyelination. Using the mouse model, we show that the low steady state levels of PLP result from accelerated proteasomal degradation rather than decreased synthesis. The T(1/2) for degradation of rumpshaker PLP is 11 h compared with 23 h for wild type. A minority of newly synthesized PLP is incorporated into myelin in the correct orientation but at a reduced rate compared with wild type. However, inhibition of proteasomal degradation does not increase the level of PLP incorporated into myelin. As Plp null mice do not have a similar myelin deficiency, it is unlikely that the reduced PLP levels are the main cause of the dysmyelination. Rumpshaker oligodendrocytes also have a reduced level of other myelin proteins, such as MBP, although the mechanisms are not yet defined but are likely to operate at a translational or post-translational level.     

Decreased brain N-acetylaspartate in Huntington''s disease.

The concentration of N-acetylaspartic acid (NAA) was measured in perchloric acid extracts of postmortem brain tissue obtained from patients with Huntington's disease and from control subjects. The material in the desalted extracts was resolved on an ion exclusion column and the content of NAA was determined by subsequent fluorometric quantitation of aspartate in hydrolyzates of the resolved NAA. The concentration of NAA in the putamen from patients with Huntington's disease was less than half that of controls (2.74 vs. 6.06 μmol/g wet weight). A smaller but significant reduction was also evident in samples of cerebral cortex from Brodmann area 10 (3.99 vs. 5.29 μmol/g), while the difference in concentrations in the cerebellum was not statistically significant. Though NAA could play a direct role in Huntington's disease, it seems more likely that the changes observed reflect illness or death of neurons, and that it may be feasible to monitor the course of Huntington's disease from NAA determinations. The same tissue extracts were also examined for the presence of d-isomers of amino acids. Only traces were found in NAA, aspartate, or glutamate.     

Disturbances of rapid-eye-movement sleep in 3 brothers with Pelizaeus-Merzbacher disease.

The electrophysiological features of 3 brothers with the classic form of Pelizaeus-Merzbacher disease (PMD) were studied. Two consecutive overnight polygraphic sleep recordings indicated a gross distortion of rapid-eye-movement (REM) sleep for all patients. A lower than normal percentage of REM sleep in these patients was consistent with their retarded intellectual development, which supports current thinking that REM sleep may be a sensitive index of brain function integrity. Non-rapid-eye-movement (NREM) sleep, in contrast to reported findings in 1 patient with PMD, was uniformly characterized by distinct stages in which the electroencephalograms contained frequent vertex waves and spindles. Tests of peripheral nerve conduction velocity, acoustic brainstem reflexes, and visual and auditory evoked potentials did not indicate any abnormalities, nor did electroencephalograms obtained during wakefulness. One patient did have epileptiform spikes and spike waves recorded during an all-night EEG, an unusual finding in a child with cerebral white matter disease.     

Clinical findings in Pelizaeus-Merzbacher disease

Pelizaeus-Merzbacher disease is a rare X-linked disease characterized by defective central nervous system myelination owing to a mutation in the proteolipid protein 1 gene. Few studies report detailed clinical findings in children with genetic confirmation of mutations in the proteolipid protein 1 gene. We reviewed the records of 10 boys with Pelizaeus-Merzbacher disease and one symptomatic carrier girl. Their median age was 2 1/2 years (range 10 months to 20 years). Nine had proteolipid protein 1 gene duplications, one had a point mutation, and one had a single codon deletion. The families of eight patients reported perinatal complications, including maternal hypertension (three patients) and meconium aspiration (three patients). All of the patients were social and interactive, but all had difficulty with expressive speech. All patients presented with nystagmus and had hypotonia that progressed to spasticity, affecting the legs more than the arms; ataxia also contributed to motor impairment. Additional problems reported regarded feeding (eight patients) and sleep (three patients). Further work is needed to clarify the variations in disease course and the relationship of genotype to phenotype.     

Neurophysiological study in Pelizaeus-Merzbacher disease

The neurophysiological characteristics of Pelizaeus-Marzbacher disease (PMD) were studied in four Japanese patients aged between 5 and 13 years. Pendular spontaneous nystagmus was always recorded with a frequency between 2.5 and 4 Hz, and abnormal saccades with an almost twofold prolongation in onset time and 50% decrease in velocity were noted. Brainstem auditory evoked potentials consistently demonstrated severely altered waves II to V, following a normal wave I, despite normal hearing acuity. Somatosensory evoked potentials (SEPs) were always absent between brainstem components and early cortical responses. Late cortical components of SEPs and visual evoked potentials with significantly prolonged latencies were recorded in the three younger cases having normal sensory and visual acuity (N35 of SEP, 73.1 ± 2.1 ms; N75 of VEP, 129.0 ± 12.7 ms; mean ± S.D.), while these peaks were absent in the oldest case having the most severe handicap. In motor evoked potentials (MEPs), R1 of blink reflex with significantly prolonged latency (14.9 ± 1.48 ms) was always obtained, and no subsequent R2 was elicited. Magnetic transcortical stimulation elicited no MEPs of the thenar even in the facilitating condition on voluntary contraction despite mild weakness of the thenar, while normal MEPs were always elicited on cervical stimulation. These electrophysiological findings were consistent with extensive conduction slowing involving the brainstem to the cerebrum, which seemed to be accompanied by conduction block in motor systems rather than sensory systems. Although each of the results was not specific, in combination they suggested the characteristics of diffuse brain dysmyelination in PMD.     

Microcephaly with peculiar demyelination mimicking Pelizaeus-Merzbacher disease

Summary The neuropathological studies of a 4-year old idiot with microcephaly revealed a striking demyelinating disease compatible with Pelizaeus-Merzbacher disease. The case seemed to be best classified as the patchy demyelination type, but the most unusual finding was a prominent vasculature in some demyelinated areas. Intrauterine hypoxia was proposed as a causative factor of this type of demyelinative lesions     

Pelizaeus-Merzbacher disease, Pelizaeus-Merzbacher-like disease 1, and related hypomyelinating disorders

The purpose of this article is to present contemporary information on the clinical and molecular diagnosis and the treatment of Pelizaeus-Merzbacher's disease (PMD) and related leukodystrophies. Various types of mutations of the X-linked proteolipid protein 1 gene (PLP1) that include copy number changes, point mutations, and insertions or deletions of a few bases lead to a clinical spectrum from the most severe connatal PMD, to the least severe spastic paraplegia 2 (SPG2). Signs of PMD include nystagmus, hypotonia, tremors, titubation, ataxia, spasticity, athetotic movements and cognitive impairment; the major findings in SPG2 are leg weakness and spasticity. A diffuse pattern of hypomyelination is seen on magnetic resonance imaging (MRI) of PMD/SPG2 patients. A similar constellation of signs and pattern of hypomyelination lead to the autosomal recessive disease called Pelizaeus-Merzbacher-like disease 1 (PMLD1) and the less-severe spastic paraplegia 44 (SPG44), caused by mutations of the gap junction protein, gamma-2 gene (GJC2), formerly known as the gap junction protein, α-12 gene (GJA12). Magnetic resonance spectroscopy (MRS) and brainstem auditory evoked potentials (BAEP) may assist with differential clinical diagnosis of PMD and PMLD1. Supportive therapy for patients with PMD/SPG2 and PMLD1/SPG44 includes medications for seizures and spasticity; physical therapy, exercise, and orthotics for spasticity management; surgery for contractures and scoliosis; gastrostomy for severe dysphagia; proper wheelchair seating, physical therapy, and orthotics to prevent or ameliorate the effects of scoliosis; special education; and assistive communication devices.     

Magnetic resonance imaging in Pelizaeus-Merzbacher disease

Cranial computed tomography of a boy with clinical characteristics of the classic form of Pelizaeus-Merzbacher disease did not reveal a notable abnormality other than enlarged ventricles. Magnetic resonance imaging, however, demonstrated diffuse changes in the white matter with sparing of scattered small areas, suggesting persistent myelin islands which are a typical neuropathologic finding in Pelizaeus-Merzbacher disease. Magnetic resonance imaging appears more useful than computed tomography in confirming the diagnosis of Pelizaeus-Merzbacher disease.     

Initial semeiology in children with Charcot-Marie-Tooth disease 1A duplication

The aim of this study was to describe the initial signs and symptoms in Charcot-Marie-Tooth disease type 1A (CMT-1A). Twelve secondary cases with CMT-1A were serially evaluated. Ages at initial clinical examination ranged between 1 month and 5 years (mean, 2 years) and final ages between 6 and 23 years (mean, 13 years). First signs of the disease were detected at initial or upon serial examinations in all 12 patients at ages ranging between 1 and 10 years (median, 4 years). The most frequent signs were lower limb areflexia in 12, difficulty in heel walking in 8, nerve enlargement in 6, atrophy of intrinsic foot muscles in 6, clawing of toes in 5, pes cavus or cavus varus in 4, shortening of Achilles tendon in 3, peroneal weakness in 1, and stocking hypoesthesia in 1. Only three patients were symptomatic at the initial evaluation. We conclude that initial CMT-1A signs usually appear in early childhood, although they may be quite subtle and require serial examinations for detection. Lower limb areflexia is the only constant early sign.     

Amphetamine exposure is elevated in Parkinson's disease

BACKGROUND: Since the 1930's, amphetamine drugs have been used therapeutically and recreationally. High doses are associated with acute injury to axon terminals of dopaminergic neurons. It is unknown whether low dose exposure to amphetamine over a prolonged time period is associated with the development of Parkinson's disease (PD). METHODS: A telephone survey of drug and chemical exposure was administered to patients from three faculty practice clinics at UCSF. Patients were asked to participate if they had been diagnosed with peripheral neuropathy (PN), amyotrophic lateral sclerosis (ALS), or PD between the ages of 40 and 64. Spouses or caregivers were also asked to participate. "Amphetamine exposure" was defined as a prior use of amphetamine, methamphetamine or dextroamphetamine. "Prolonged exposure" was defined as amphetamine use that occurred more than twice a week for > or =3 months or weekly usage for > or =1 year and had to occur before diagnosis of the neurological condition. RESULTS: Prolonged exposure to either prescribed or non-prescribed amphetamine was common, occurring in 15% with PN (11/76), 13% with ALS (9/72), and 11% with PD (17/158). Prolonged amphetamine exposure was more frequent in diseased patients compared to spouses when all diseases were combined (adjusted OR=3.15, 95% CI 1.42-7.00, p=0.005). When tested alone, only the Parkinson's disease group retained statistical significance (adjusted OR=8.04, 95% CI 1.56-41.4, p=0.013). For most individuals, exposure occurred long before diagnosis (averages: PN 25 years, ALS 28 years, and PD 27 years). CONCLUSIONS: The elevated rate of prolonged amphetamine exposure in PD is intriguing and bears further investigation.