Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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Pelizaeus-Merzbacher disease and the allelic disorder spastic paraplegia 2 (SPG2) are hereditary leukodystrophies caused by mutations of the proteolipid protein 1 (PLP1) gene. The clinical syndromes range from the severe connatal Pelizaeus-Merzbacher disease syndrome, characterized by congenital hypotonia, nystagmus, and stridor, to an uncomplicated spastic paraparesis syndrome. Mutations of the PLP1 gene on the X chromosome include deletion, duplication, triplication, and quadruplication of the entire gene, as well as intragenic mutations and complex rearrangements of the gene and neighboring loci. The nature of the mutation plays an important role in determining the cellular effects on oligodendrocytes, disease severity, and pattern of inheritance. In this article, the author describes the clinical features and complex molecular genetics of Pelizaeus-Merzbacher disease and spastic paraplegia 2.
Pelizaeus-Merzbacher disease has historically been subdivided into clinical variants based on the age of onset and severity of clinical signs. "Classical" Pelizaeus-Merzbacher disease is the most common presentation and is that described by Pelizaeus (62) and Merzbacher (50). The "connatal" form of Pelizaeus-Merzbacher disease was described later and denotes clinically evident onset within the first few weeks of life and a more severe syndrome (68). Seitelberger described a “transitional” form of Pelizaeus-Merzbacher disease that was intermediate in clinical severity between connatal and classical disease (69). In 1964, Zeman and colleagues pointed out that Pelizaeus-Merzbacher disease is a dysmyelinating, rather than a demyelinating, entity and stressed the importance of clinical observation and the familial nature of the disorder rather than strict pathological criteria to define the condition (94). They also hypothesized that the defect in Pelizaeus-Merzbacher disease affected a myelin proteolipid. Saugier-Veber and colleagues discovered that some families with X-linked spastic paraparesis have PLP1 mutations (66). It must be noted that these syndromes overlap.
Notes on nomenclature. Gene names are italicized, whereas the protein names or abbreviations are not. The PLP1 gene was previously called the PLP gene but was renamed after discovery of a similar gene that was named PLP2. The protein is still abbreviated PLP, however. Historically, the numbering of PLP1 amino acids began with the glycine because the initiation methionine is post-translationally excised. The numbering of nucleotides has followed this convention in the past but should now conform to more accepted conventions, with numbering starting at the initiation codon and initiation methionine, as specified by the Human Genome Variation Society.
Clinically, Pelizaeus-Merzbacher disease has been classified into 3 subtypes according to the age of presentation (71): type I, or classic Pelizaeus-Merzbacher disease; type II, or connatal form; and type III, or transitional Pelizaeus-Merzbacher disease (60). The disease is evident usually in the first few months of life, but it occasionally presents later. The precise findings vary with age. Nystagmus is the most common and earliest sign and may be noted at birth, even in patients with SPG2. Therefore, neonatal onset of nystagmus by itself does not necessarily indicate a connatal syndrome. The eye movements may have a distinctive rotary component, but horizontal and vertical movements occur. Abnormal eye movements often dissipate with age. Because the nystagmus occurs at a time important for development of the visual system, we speculate that the visual impairment observed clinically in many patients results from this oculomotor abnormality as well as from optic nerve dysmyelination. Psychomotor development is usually delayed, although many may learn to talk, and a few have attended school and held employment (SPG2 end of the spectrum). At least in some cases, apparent mental retardation may owe more to motor than to intellectual deficits. It is important to take great care in assessing receptive language in these patients who may have good understanding in spite of limited or absent expressive language. In carrier females, dementia may be a late manifestation, although there are not yet enough cases for a firm conclusion (63; 56). Inability to hold the head erect and titubation may be noted. Ataxia and spasticity progressing to spastic diplegia are universal, and patients may show dystonia. Most patients never walk, but some patients may be able to walk short distances with assistance. Patients who do achieve useful independent ambulation, even if for just a few years, would be considered to have spastic paraplegia 2.
Laryngeal stridor at birth that improves with time, which may resemble vocal cord paralysis (90), probably occurs more often than is appreciated and is typical in patients with the most severe “connatal” form of Pelizaeus-Merzbacher disease (06; 14). Seizures during infancy also are common in patients with connatal disease, but later onset seizures occur in some patients with less severe syndromes. Early onset respiratory insufficience can be a presenting sign in the connatal form of Pelizaeus-Merzbacher disease (83). Episodic spells, which typically include tonic spasms, may respond well to antiepileptic medications even though no evidence for seizures can be recorded concurrently on scalp electroencephalograms.
Most patients clinically plateau after reaching a developmental peak, typically during late childhood or early adolescence. Apparent disease progression may result from contractures that develop with time, especially in patients with the classical syndrome. Some patients, however, do progress more rapidly than others. Patients with the PLP1 null syndrome, whose mutations prevent expression of PLP, typically have a complicated spastic paraplegia phenotype that leads to loss of ambulation and impaired cognitive function during late adolescence or early adulthood (19). These patients also have electrophysiologic evidence for mild, non-uniform demyelinating peripheral neuropathy (72).
Patients with pure, or uncomplicated, SPG2 generally develop spastic paraparesis during childhood. Nystagmus may be present during infancy, but is not as consistently seen as in patients with Pelizaeus-Merzbacher disease. Neurogenic bladder symptoms are also common. In addition to the gait and bladder signs, patients with complicated SPG2 may have one or more additional CNS signs such as cognitive impairment, ataxia, visual impairment, or dysarthria. The gait usually deteriorates during adolescence or early adulthood, and patients typically become wheelchair-dependent during adulthood.
Gorman and colleagues reported a child who had normal early neurologic development but subsequently developed relapsing and remitting neurologic signs and multifocal white matter lesions and oligoclonal bands in the cerebrospinal fluid. Corticosteroid treatment clinically appeared to ameliorate neurologic signs and symptoms. It was speculated that the child’s PLP1 missense mutation predisposed him to immune-mediated demyelination, and this raises the possibility that some instances of acute demyelinating encephalomyelitis and multiple sclerosis may be due to or predisposed by mutations in PLP1 or possibly other myelin protein genes (22).
On physical examination, small head size, horizontal, elliptical, pendular, or rotary nystagmus, titubation, spasticity, ataxia, and in older patients, scoliosis and joint contractures will be found in most patients. The Babinski sign and hyperreflexia are present. Funduscopy shows optic discs that range from pale to frankly atrophic by age 6 years (06). Patients with SPG2 have Babinski signs, hyperreflexia, leg spasticity, and spastic gait with additional central neurologic signs if their disease is of the complicated type.
Family and individual histories are an important component of the diagnostic workup, as recognized by Zeman (94) and Boulloche and Aicardi (06). It is important to inquire about a history of cerebral palsy, the most common misdiagnosis, and about other neurologic disorders that might have been confused with Pelizaeus-Merzbacher disease in other relatives. Diagnosis is more difficult but remains possible without a positive family history. Male-to-male disease transmission within a family excludes the diagnosis of Pelizaeus-Merzbacher disease, however. Although signs and symptoms within a family are often consistent, onset and findings may vary among family members. Thus, a child with classical Pelizaeus-Merzbacher disease may appear in a family with spastic paraplegia (55).
The prognosis in early-onset severe (connatal) Pelizaeus-Merzbacher disease is generally poor. Cognitive development in affected males is poor; the patients are largely immobile, and death typically occurs by the end of the second decade. Feeding tubes may be needed for children with severe dysphagia and frequent aspiration episodes to minimize episodes of pneumonia as well as to provide nutrition. Constipation and neurogenic bladder are common complications, probably caused by the underlying myelination defect, but relative immobility likely contributes to the constipation. Patients with spasticity often progress to develop joint contractures that usually are worse in the legs, and scoliosis, sometimes severe enough to restrict breathing, may develop. Some patients with later onset of disease may be afflicted more mildly, and a few have been able to attend regular schools, including college, and obtain regular employment. This is especially true in spastic paraplegia 2 or less severely affected Pelizaeus-Merzbacher disease patients. Female carriers are almost always asymptomatic or only mildly affected, usually with spastic paraparesis.
A mother noted continuous eye movements in her son when he was about 2 months old. The child had poor head control at 4 months of age, but he smiled socially. Motor development was slow; he rolled over at 15 months and was never able to sit upright without support.
He had acquired some speech by 4 years of age but was very dysarthric, and he was placed in special education early intervention classes after being diagnosed with cerebral palsy. He made slow developmental progress, but he was referred to a pediatric neurologist for reevaluation due to worsening leg spasticity.
At age 12 years, his verbal comprehension was good, and he could speak short sentences with dysarthric speech and sometimes needed to repeat himself to be understood. He could read large type but not small letters, and optic discs were pale. He had subtle nystagmus but conjugate eye movements. He had poor head control and titubation. The child could not sit without support or walk and had very ataxic voluntary movements of the arms and very little voluntary movements of the legs, which were spastic. His mother’s sister had a 1-year-old son who had nystagmus, hypotonia, and developmental delay.
Brain MRI showed diffuse T2 hyperintensity in the cerebral, cerebellar, and brainstem white matter with typically normal white matter signal on T1-weighted images. Absent central conduction was demonstrated by brainstem auditory evoked response testing, and visual evoked response latencies were very prolonged, although peripheral nerve conduction velocities were normal.
Pelizaeus-Merzbacher disease is caused by mutations affecting the PLP1 gene (16; 17). Although PLP1 point mutations were the first to be shown to cause Pelizaeus-Merzbacher disease (21; 34; 82), it is now clear that segmental X chromosome duplications that span the PLP1 gene are the most common cause of Pelizaeus-Merzbacher disease (36; 75; 52), whereas only 15% to 20% have mutations within the exons or flanking intronic regions of the gene (05; 57; 52; 28). Triplication and even quintuplication of PLP1 has been found to cause Pelizaeus-Merzbacher disease, and the severity of disease appears to correlate with the extra gene dosage (91). One child with an X chromosome inversion but with a single PLP1 gene has been reported with a Pelizaeus-Merzbacher disease phenotype (53). The authors speculate that one of the inversion breakpoints juxtaposed regulatory elements from a heterologous gene close enough to the PLP1 gene to cause overexpression of PLP1. Complete or partial deletion of the PLP1 gene is the least common cause of Pelizaeus-Merzbacher disease, and fewer than 5 families have been reported worldwide. These proportions of mutation types are seen in both familial and sporadic Pelizaeus-Merzbacher disease (52). Some mutations cause frame shifts of the reading frame during protein translation, and an increasing number of mutations are recognized at splice sites or in the noncoding regions of the PLP1 gene (28; 29). The duplications of the PLP1 locus appear to occur by a mechanism distinct from that that causes duplication of the PMP22 gene in Charcot-Marie-Tooth disease 1A (CMT1A). Whereas flanking, low-copy-repeats mediate non-allelic homologous recombination in patients with CMT1A (64), this is not the case with PLP1 duplications, where the mechanism appears to be that involving DNA breakage and repair with non-homologous end-joining (92). Although this mechanism can account for some of the observed duplications, more complex rearrangements have also been described; a mechanism that invokes aberrant DNA replication is the most parsimonious explanation. This mechanism, termed Fork-stalling and Template Switching (FosTeS), may cause not only the complex rearrangements that can cause Pelizaeus-Merzbacher disease but also copy number variation elsewhere in the human genome (44; 95). Duplications most likely arise in male germ cells (ie, in the maternal grandfather of a “new mutation” patient), whereas point mutations probably can arise through either male or female germ cells (52). Remarkably, several subjects have been described who have the duplicated PLP1 gene translocated to distant loci on the X chromosome or even to heterologous chromosomes (32; 37).
Great reduction or absence of myelin, resulting from variable degrees of oligodendrocyte death or dysfunction caused by PLP1 mutation, in the CNS is the chief cause of the neurologic disturbances, as reviewed in (17). There is evidence that the severity of the disease correlates with faulty trafficking of PLP1 and DM20 through the endoplasmic reticulum (23). Mutations that cause misfolding and prevent plasma membrane incorporation of both PLP1 and DM20 induce oligodendrocyte apoptosis, via elements of the unfolded protein response (77; 24). These mutations clinically are associated with connatal Pelizaeus-Merzbacher disease. Less severe mutations seem to cause less disruption on oligodendrocyte survival and function, but other effects, such as reduced PLP1/DM20 stability and impaired membrane assembly due to impaired binding of the mutant PLP1/DM20 to cholesterol and lipid, may contribute to disease pathogenesis (43). However, prolongation of oligodendrocyte survival with a compound that modulates the ER stress response and rescues mutant oligodendrocyte in the jimpy mouse did not restore myelination, suggesting other mechanisms for lack of myelination in PLP1 mutants (13). PLP1 duplications presumably cause overexpression of PLP1 and DM20. PLP1 overexpression also appears to cause a degree of oligodendrocyte cell death, although the mechanism probably differs from that which causes connatal disease (74). Investigators found PLP1 mutations lead to iron-induced cell death through lipid peroxidation, abnormal iron metabolism, and hypersensitivity to free iron (59). Iron chelation rescued oligodendrocytes from cell death, thus, suggesting a therapeutic approach to the disease in the preclinical stage. Mice that overexpress PLP1 develop cerebral inflammation that is ameliorated when the immune system is genetically ablated (39). If a similar inflammatory response occurs in humans, anti-inflammatory treatments might be of therapeutic benefit in Pelizaeus-Merzbacher disease patients. Clear-cut structure-function relationships are not identifiable; however, mutations in evolutionarily more highly conserved regions of the protein are associated with more severe clinical disease (08). Pathologically, in the "classical" form of the disease, myelin islands or tigroid myelination may be found (70; 33). A mouse overexpressing the PLP1 showed abnormal mitochondrial function and increase oxidative stress (65).
Patients with the PLP1 gene-null syndrome, caused by mutations that prevent expression of both the PLP1 gene and DM20, develop late onset neurologic deterioration that usually begins in early adulthood. This deterioration most likely results from axonal degeneration and can be inferred by magnetic resonance spectroscopy (19). Similar axonal changes were found in mice deficient for PLP1 and DM20 and demonstrate the importance of oligodendrocytes in maintaining the integrity of axons and of the myelin sheath (25). Impaired axonal transport has been shown experimentally in PLP1-null mice (12).
Mutations affecting PLP1 can cause not only axonal degeneration but also neuronal loss, particularly in the cerebellum (73). The mechanisms for this neuronal loss are unclear but demonstrate that glial integrity is also important for maintaining neuronal viability. The use of induced pluripotent cells with secondary differentiation to oligodendrocyte progenitors in culture identified 3 distinct classes of cellular defects in PMD-derived oligodendrocytes: failure to produce oligodendrocytes, failure to produce PLP1+ oligodendrocytes, and perinuclear retention of PLP1 (58). Perinuclear localization is a hallmark of protein misfolding and ER retention.
The disease is usually limited to the CNS, where PLP1 is the chief protein component of myelin, but peripheral nerve involvement has been found in patients whose mutations prevent full-length PLP1 gene expression (18; 72). Mutations that disrupt the PLP1 gene-specific domain (residues 116 to 150) as well as null mutations cause mild, demyelinating peripheral neuropathy (72). Thus far, only 1 family with a PLP1 gene mutation lying distal to the proteolipid protein-specific region has been reported with peripheral neuropathy (87).
Female heterozygotes may have persistent neurologic signs, including those typical of Pelizaeus-Merzbacher disease. In cases where the signs are transient, the likely explanation comes from clinical observations and studies in animals with PLP1 mutations and is based on 2 phenomena that play important biological roles: oligodendrocyte apoptosis caused by mutant PLP1 (discussed above) and X-inactivation (04; 31; 11; 38). X-inactivation is the phenomenon that occurs during fetal development in females whereby one X chromosome is permanently inactivated in any given cell and all its subsequent progeny. Thus, a female’s body is a mosaic of cells that are using one or the other X chromosome. In a young female heterozygote, neurologic signs may occur before the dying oligodendrocytes are replaced by those that are using the normal X chromosome. When the oligodendrocytes using the abnormal X chromosome have been replaced by healthy ones, the neurologic signs disappear. Skewed X-inactivation (with disproportionate inactivation of the normal X chromosome) may account for those females with a more severe and persistent disease that does not resolve over time. Indeed, Pelizaeus’ original family had at least 2 affected females. In contrast, the clinical observation that the vast majority of females heterozygous for the PLP1 gene duplication are normal may be due to skewed inactivation of the abnormal X chromosome (93).
The inheritance pattern is X-linked and most often recessive. However, some families have a large number of female patients, and in these expression may be codominant (18; 30; 35). Typically in these families, affected males have a clinically less severe syndrome. In these cases, PLP1 gene mutations are thought to cause little or no death of oligodendrocytes; therefore, they persist in female heterozygotes and, thus, can lead to neurologic signs and symptoms, usually spastic paraparesis (31; 18; 76; 35). In this situation, the inheritance pattern could be considered X-linked dominant, although there may be reduced penetrance.
Little is known, but the disease has been reported throughout the world in all major racial groups. The most comprehensive epidemiologic survey of leukodystrophies, conducted in Germany, found the incidence of Pelizaeus-Merzbacher disease to be 1 per 770,000 live births (26). The authors acknowledged that their figures could underestimate the frequencies of leukodystrophies by up to 250%. In the Czech republic, the incidence may be as high as 1 per 90,000 births (67). With a conservative assumption that Pelizaeus-Merzbacher disease patients survive 10 years, the prevalence of Pelizaeus-Merzbacher disease could be at least 1/50,000 to 1/100,000.
When a mutation or duplication in the PLP1 gene has been demonstrated, prenatal When a mutation or duplication in the PLP1 gene has been demonstrated, prenatal diagnosis, and preimplantation genetic diagnosis, can be offered (15; 88). When there is no demonstrable mutation or duplication, but sufficient informative family members, linkage analysis may be helpful for prenatal and preimplantation genetic diagnosis (46; 07; 05; 51; 88). Genetic counseling is essential in any case.
A family history consistent with X-linked transmission makes the diagnosis easier. However, because new mutations occur, a family history of Pelizaeus-Merzbacher disease is not essential. Uhlenberg and colleagues demonstrated that an autosomal recessive syndrome with clinical features otherwise highly similar to Pelizaeus-Merzbacher disease was caused by mutations in the gap junction C2 (GJC2, formerly GJA12) gene (84). The differential diagnosis is also age-dependent. In the newborn period through infancy, cerebral palsy, spasmus nutans, opsoclonus-myoclonus syndrome, mass lesions, congenital nystagmus, and the other leukodystrophies are the chief considerations. Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus-Merzbacher disease (54).
X-linked early onset hypotonia with nystagmus, developmental delay, and severe mental retardation with white matter abnormalities on MRI can be caused by mutations in the SLC16A2 (formerly MCT8) gene (86). This syndrome is unusual in that the MRI white matter changes improve over time, even though the clinical syndrome gradually worsened. Mutations in this gene are also responsible for the Allan-Herndon-Dudley syndrome. Dysmorphic facial appearance with elongated facies, bitemporal narrowing, and large, simple external ears along with pectus excavatum are characteristic of this syndrome. The SLC16A2 protein is important for T3 uptake by cells, and the syndrome is strongly suggested if thyroid studies show elevated T3 levels, but decreased T4 and normal thyroid-stimulating hormone levels. Therapeutic trials with supplemental T4 has not been helpful, suggesting a specific deficiency of T3 in the CNS. Therapies to increase T3 to the brain have not yet been reported but potentially could be effective for this disease.
An autosomal recessive syndrome that is clinically characterized by early hypotonia, developmental delay, and mental retardation progressing to severe spastic quadriparesis, fatal during childhood or adolescence, was found in an Israeli Bedouin family to be caused by a homozygous mutation in the HSPD1 gene that encodes the mitochondrial hsp60 protein (47).
Cerebral palsy, the most common misdiagnosis applied to children with Pelizaeus-Merzbacher disease, must be considered in the differential (01). Titubation and truncal ataxia may be seen in both Pelizaeus-Merzbacher disease and cerebral palsy, but a severely or predominantly ataxic clinical picture argues against a diagnosis of cerebral palsy. Clinical deterioration may occur in patients with Pelizaeus-Merzbacher disease, but this does not occur, by definition, with static encephalopathy.
Spasmus nutans consists of a triad of nystagmus, head nodding, and anomalous head positioning without other neurologic abnormalities (42). The nystagmus is either monocular or, when present in both eyes, asymmetric, whereas nystagmus in Pelizaeus-Merzbacher disease is symmetrical.
The other leukodystrophies differ from Pelizaeus-Merzbacher disease in several ways. Many are demyelinating rather than dysmyelinating disorders and, therefore, often show later onset and more rapid progression, whereas Pelizaeus-Merzbacher disease is usually of early onset and typically stationary or gradually progressive. Serum lysosomal enzymes, N-acetylaspartate levels, very long chain fatty acids, organic acids and urinary sialic acid levels should be measured to rule out Krabbe and Canavan diseases, Tay-Sachs disease, metachromatic leukodystrophy, adrenoleukodystrophy, L-2-hydroxyglutaric aciduria, and Salla disease. Adrenoleukodystrophy usually has later clinical onset, and MRI scans show occipital white matter changes. Metachromatic leukodystrophy usually presents with frontal white matter changes. Interestingly, although enlargement of the optic nerves is a feature of Krabbe disease, a patient with Pelizaeus-Merzbacher disease with enlarged optic nerves has been described (61). Magnetic resonance spectroscopy in patients with Pelizaeus-Merzbacher disease is normal in most cases, whereas Canavan disease causes greatly elevated N-acetylaspartate levels. Patients with vanishing white matter disease (also known as childhood ataxia with central hypomyelination) often have clinical worsening after febrile illness or traumatic head injury. This disorder is caused by mutations in subunits of the translation initiation factor eIF2B (85). Except for the X-linked adrenoleukodystrophy, these disorders are autosomal recessive.
X-linked spastic paraplegia may or may not be caused by mutations in the PLP1 gene. X-linked spastic paraplegia is generally of later onset than is Pelizaeus-Merzbacher disease, and its signs may be limited to the legs. When the eyes and other parts of the nervous system are involved, there may be no sure way of delineating the conditions; however, abnormal white matter on MRI scans is usually found in cases due to PLP1 gene mutations and should prompt a search for PLP1 mutation.
Mental retardation, aphasia, shuffling gait and adducted thumbs (MASA) syndrome is characterized by dysmorphic features as well as the mental retardation, aphasia, shuffling gait, adducted thumbs, and, sometimes, hydrocephalus in addition to the spastic paraparesis, but white matter MRI abnormalities are not typically found in this disease. The condition is linked to Xq28 and caused by mutations in the L1CAM gene (89).
Cockayne syndrome should be readily distinguishable because of the beaked nose, large ears, skeletal changes, retinal pigmentation, cataract, and deafness. It is caused by mutations affecting 1 of at least 2 DNA repair enzymes (27; 48). It is sometimes included with the leukodystrophies because of formal similarities of the neuropathological findings with those of Pelizaeus-Merzbacher disease (69).
Some patients with Pelizaeus-Merzbacher disease and dysmorphic features have complex rearrangements that include duplications of the PLP1 gene locus (10; 09; 32).
When present, a family history of Pelizaeus-Merzbacher disease, X-linked spastic paraplegia, or "cerebral palsy" is most helpful. The individual history of early-onset nystagmus (particularly rotary), respiratory stridor, and the other clinical signs is important, especially in older individuals who may no longer manifest these findings. A magnetic search-coil study may be necessary to resolve the nature of the nystagmus (81).
Because Pelizaeus-Merzbacher disease is a leukodystrophy, MRI will usually show a uniformly increased intensity of the white matter signal in T2-weighted images (41). However, this abnormality is best appreciated in children over about 1 year of age. Myelination is still actively ongoing until much later in life, and MRI is less useful in diagnosing young infants; however, in a normal newborn there should be myelination in the posterior limb of the internal capsule and brainstem (02). Therefore, with the appropriate clinical syndrome of neonatal nystagmus and hypotonia, lack of myelination in these areas should suggest the diagnosis of Pelizaeus-Merzbacher disease. At later stages of the disease, atrophy of the brain is sometimes visible in the scans. Carriers have normal or near-normal MRI scans. CT scans are not useful for diagnosis, although they may show mild signs of brain atrophy. One exceptional family has intracerebral calcifications and cystic changes in the white matter (03). Patients with pure spastic paraplegia 2 may have normal or only mildly abnormal white matter on MRI scans.
Nerve conduction velocity studies generally are normal, but patients with the PLP1 null syndrome or with mutations affecting the PLP1-specific region may have mild demyelinating polyneuropathy (18; 72). Evoked potentials, particularly the brainstem auditory evoked potential and visual evoked potentials, are characteristically abnormal, with delay or disappearance of the central components (49; 20). Magnetic resonance spectroscopy (MRS) may show slight elevation of cerebral white matter N-acetyl aspartate (NAA) levels (79), suggesting Canavan disease, but in the absence of macrocephaly and rapid clinical deterioration and seizures, and with nystagmus and normal urine and serum NAA, the diagnosis of Pelizaeus-Merzbacher disease should be considered. MRS may be reduced in cerebral white matter, and if combined with a mild demyelinating peripheral neuropathy and diffuse leukodystrophy on MRI, the PLP1 null syndrome should be considered.
When the history, clinical examination, and other examinations indicate a strong possibility of Pelizaeus-Merzbacher disease, lymphocytes or other cells should be subjected to DNA analysis. Because duplications of the PLP1 gene are the most common cause of Pelizaeus-Merzbacher disease, it is reasonable to begin with duplication testing by fluorescent in situ hybridization analysis. Fluorescent in situ hybridization analysis may suggest the possibility of a complex chromosomal rearrangement, which should prompt a full high-resolution karyotype analysis. If a duplication is not found, then quantitative polymerase chain reaction or multiple ligation probe amplification (91) testing should be performed to identify patients with duplications too small to resolve by fluorescent in situ hybridization analysis. Several patients have been reported to have duplications by florescent in situ hybridization analysis, but testing by quantitative PCR reveals the PLP1 gene is not duplicated (unpublished observations). Therefore, ideally both fluorescent in situ hybridization analysis and quantitative polymerase chain reaction testing should be obtained because they complement each other. If duplications are excluded then a search for mutations within the PLP1 gene should be requested. The diagnosis of Pelizaeus-Merzbacher disease is confirmed when a mutation in, or duplication of, the PLP1 gene is found. If the clinical syndrome is consistent with both autosomal recessive inheritance and Pelizaeus-Merzbacher disease, testing for GJC2 (formerly GJA12) mutations should be entertained.
Management varies with the age of the patient and is largely symptomatic. Periodic evaluations and therapy with developmental pediatricians and physiatrists are important to provide for educational needs and to minimize the development of severe contractures or scoliosis. These complications may be minimized with physical therapy and antispasticity medications. Botulinum toxin injections or intrathecal baclofen may be helpful, especially in patients who cannot tolerate high oral dosages of medication and who respond well to a test intrathecal trial. Swallowing and speech therapy should be arranged as needed, and severe feeding and respiratory difficulties may necessitate gastrostomy tube feeding or tracheostomy, respectively. Use of stool softeners, mild laxatives, and enemas may be needed for bowel management. Severely affected patients remain bedridden for life and require complete care. Those patients who manifest chiefly with spastic paraplegia may manage well with occasional help. Seizures or seizure-like spasms may respond to antiepileptic agents such as carbamazepine, phenytoin, or valproate.
Understanding of the disease mechanism leads to the development of novel therapeutic approaches such as presymptomatic iron chelation (59), ketogenic diet (78), and downregulation of the overexpressing PLP1 gene (45).
Genetic counseling should be provided to affected families. As noted above, in most families, Pelizaeus-Merzbacher disease usually follows an X-linked recessive pattern, but especially in families affected by spastic paraplegia 2 or milder Pelizaeus-Merzbacher disease as in the PLP1 null syndrome, the syndrome may be more accurately characterized as X-linked dominant with reduced penetrance. Prenatal and preimplantation genetic testing is available in mutation-confirmed cases (15; 88).
Some mildly affected females have borne children, but most heterozygous females are healthy and do not have increased pregnancy complications.
The type of anesthesia, induction, etc. are determined more by associated conditions, such as seizures and gastroesophageal reflux, than by Pelizaeus-Merzbacher disease itself (80). The difficulties and the approach to anesthesia in Pelizaeus-Merzbacher disease has been described, indicating a possible combination of general and regional anesthesia (40).
This article is dedicated to the memory of Dr M E Hodes and his many contributions to our understanding of Pelizaeus-Merzbacher disease.
Raphael Schiffmann MD
Dr. Schiffmann of Baylor Scott & White Research Institute received research grants from Amicus Therapeutics, Takeda Pharmaceutical Company, Protalix Biotherapeutics, and Sanofi Genzyme.See Profile
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