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PLP1-Related Disorders

[Includes: Pelizaeus-Merzbacher Disease, Spastic Paraplegia 2]

Summary

Disease characteristics.   PLP1-related disorders of central nervous system myelin formation include a range of phenotypes from Pelizaeus-Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2). PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment; the findings progress to severe spasticity and ataxia. Life span is shortened. SPG2 manifests as spastic paraparesis with or without CNS involvement and usually normal life span. Female carriers may manifest mild to moderate signs of the disease. Intrafamilial variation of phenotypes can be observed, but the signs are usually fairly consistent within families.

Diagnosis/testing.  Clinical diagnosis of PLP1-related disorders depends on typical neurologic findings, X-linked inheritance pattern, and, usually, the finding of diffusely abnormal myelin on MRI. PLP1 is the gene most often associated with PMD and SPG2. Between 80% and 95% of males with PMD or SPG2 have an identifiable alteration in PLP1. Molecular genetic testing is clinically available.

Management.  Treatment for PLP1-related disorders involves a multidisciplinary team comprising specialists in neurology, physical medicine, orthopedics, pulmonary medicine, and gastroenterology. Treatment may include gastrostomy for individuals with severe dysphagia; antiepileptic drugs (AEDs) for seizures; and routine management of spasticity including physical therapy, exercise, medications (baclofen, diazepam, tizanidine), orthotics, and surgery for joint contractures. Individuals with scoliosis benefit from proper wheelchair seating and physical therapy; surgery may be required in severe cases. Specialized education and assessments are generally necessary, and assisted communication devices may be helpful. Surveillance includes semiannual to annual neurologic and physical medicine evaluations to monitor developmental progress during childhood and to monitor and treat spasticity and orthopedic complications as needed.

Genetic counseling.   PLP1-related disorders are most often inherited in an X-linked manner. De novo mutations have been reported. Males with the PMD phenotype do not reproduce; males with the SPG2 phenotype may reproduce. All daughters of a male proband will be carriers; no sons will inherit the mutation. All sons of a female carrier are at a 50% risk of inheriting the mutation and having the disease; all daughters are at a 50% risk of being carriers. Prenatal testing and carrier testing are possible in families in which the disease-causing PLP1 mutation has been identified or in which linkage analysis is informative.

Diagnosis

Clinical Diagnosis

The PLP1-related disorders span a continuum of neurologic findings from severe CNS involvement (PMD) to spastic paraparesis (SPG2). Although there can be intrafamilial phenotypic variability, disease signs are usually fairly consistent within families. Boulloche & Aicardi (1986), Hodes et al (1993), and Cailloux et al (2000) have summarized the clinical features of their series of individuals with PMD. The phenotypes in this spectrum cannot be neatly categorized into distinct syndromes but are summarized using designations frequently encountered in the medical literature (Table 1).

Imaging studies

Magnetic resonance imaging (MRI) is most helpful in establishing the diagnosis in those who have CNS involvement [Caro & Marks 1990 , Ono et al 1994 , Nezu et al 1998].

• PMD.  Virtually all children with the PMD phenotype have a diffuse leukoencephalopathy, best appreciated on T2-weighted or fluid-attenuated inversion recovery (FLAIR) scans. These scans show diffusely increased signal intensity in the central white matter of the cerebral hemispheres, cerebellum, and brainstem. In most children, the amount of white matter is reduced in volume and can be readily seen as thinness of the corpus callosum or general decrease in myelination [Plecko et al 2003].

  Because the bulk of myelination normally occurs during the first two years of life, the T2-weighted MRI images may not show definitive abnormalities until a child is at least age one or two years. However, a normal newborn should have myelination-related T1 and T2 signal changes in the pons and cerebellum, and a normal three-month-old infant should have evidence of myelination in the posterior limb of the internal capsule, in the splenium of the corpus callosum, and in optic radiations [Barkovitch 2005]. Absence of these early changes should raise the consideration for PMD or other dysmyelinating disorders.

• SPG2.  People with the SPG2 phenotype show less severe abnormalities on MRI scanning; they may have patchy abnormalities on T2-weighted scans or more diffuse leukoencephalopathy [Cambi et al 1995 , Hodes et al 1999].

Magnetic resonance spectroscopy (MRS) may show reduced white matter N-acetyl aspartate (NAA) levels, especially in individuals with the PLP1 null syndrome [Bonavita et al 2001 , Garbern & Hobson 2002 , Plecko et al 2003]. In contrast, individuals with PLP1 duplications may have increased white matter NAA levels and may be misdiagnosed with Canavan disease [Takanashi et al 2002]. The pattern of metabolite abnormalities in individuals with PLP1 duplication appears distinctive, with increased levels of glutamine, inositol, and creatine as well as of NAA, and may assist in the discrimination of PMD from other leukodystrophies and demyelinating diseases [Hanefeld et al 2005].

Neurophysiologic studies

The features of the nystagmus and other subtle disturbances of eye movements can be quantified and characterized with sensitive ocular movement testing [Trobe et al 1991 , Huygen et al 1992]. These features may be of diagnostic usefulness but have not been rigorously tested in a large number of affected individuals with verified PLP1 mutations.

Visual, auditory, and somatosensory evoked potential testing show normal to near-normal latencies of the peripheral component of the respective sensory modality, but severely prolonged or absent central latencies [Markand et al 1982 , Garg et al 1983 , Nezu 1995].

Except in families with PLP1 null alleles or mutations affecting the PLP1-specific region or some splice site mutations [Garbern et al 1997 , Shy et al 2003 , Vaurs-Barriere et al 2003], peripheral nerve conduction studies are normal [Wilkus & Farrell 1976]. When peripheral neuropathy is present, it is mild in comparison to the central nervous system disorder, and is characterized by mild slowing of conduction velocities that may be more pronounced across those regions of a limb susceptible to compression, such as the wrist and elbow.

Testing

Cytogenetic analysis.  Fewer than 1% of individuals with clinical features of PMD have interstitial duplications or more complex rearrangements of the X chromosome visible on routine cytogenetic studies [Cremers et al 1987 , Carrozzo et al 1997 , Hodes et al 2000].

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

Gene.   PLP1 is the gene most often associated with PMDand SPG2. Between 80% and 95% of males with PMD or SPG2 have an identifiable alteration in PLP1.

The classes of mutations that cause PLP1-related disorders are duplications, point mutations, and deletions. Triplication and quintuplication of the PLP1 gene also occur [Woodward, Kendall, Vetrie et al 1998 ; Boespflug-Tanguy et al 1999 ; Wolf et al 2005].

Other loci.  About 5%-20% of males with clinical findings consistent with the PLP1-related disorders do not have identifiable mutations in the PLP1 gene, suggesting that one or more additional autosomal or X-linked loci can cause these phenotypes [Osaka et al 1999] or that mutations occur in regions of the gene not routinely analyzed such as far upstream or downstream regions or introns.

• One autosomal gene, GJA12, causes a syndrome very similar to PMD [Uhlenberg et al 2004] (see Differential Diagnosis).
• One family with clinical features of PMD demonstrated linkage to Xq28 [Lazzarini et al 1997]. However, the observation that the duplicated PLP1 gene can be inserted elsewhere on the X chromosome might account for the failure to identify linkage to the PLP1 locus in this family and others.

Clinical uses

• Confirmation of diagnosis
• Carrier testing
• Prenatal diagnosis
• Preimplantation genetic diagnosis

Clinical testing

Duplication/deletion testing includes FISH, array genomic hybridization, Southern blot analysis, quantitative PCR, multiple ligation probe analysis (MLPA) [Wolf et al 2005 , Warshawsky et al 2006], multiplex amplifiable probe hybridization (MAPH) [Combes et al 2006], and real-time PCR [Gao et al 2005 , Hübner et al 2005 , Regis et al 2005]:

• Duplications and other gene dosage changes of variable size are found in at least 50% of males with PLP1-related disorders [Inoue et al 1996 , Woodward et al 1997 , Sistermans et al 1998 , Inoue et al 1999]; they are typically tandem duplications occurring in Xq22, which includes the entire PLP1 gene. In rare instances, the duplicated region can be inserted at some distance from Xq22; four insertions have been reported: at Xp22, Xq28 [Woodward, Kendall, Vetrie et al 1998 ; Hodes et al 2000], and 19qtel [Inoue, Osaka et al 2002] and in the Y chromosome [Woodward et al 2005 , Warshawsky et al 2006].

  Interphase FISH analysis is a sensitive method of detecting duplications; however, it is possible that some duplications may be too small to detect by conventional FISH and are better detected by other techniques such as quantitative PCR (QPCR) or quantitative Southern blot analysis. Because the probes for FISH analysis are typically quite large (>40 kbp) and include sequences that lie outside of the PLP1 gene, which is approximately 20 kbp, it is possible that FISH testing may indicate PLP1 duplication but not actually involve the PLP1 gene [Lee et al 2006]. Therefore, more direct testing of PLP1 gene duplication should be done if the clinical syndrome is not typical of a PLP1-related disorder.

  Chromosomal microarray analysis (CMA) can detect PLP1 dosage changes; however, as with the PCR-based methods, CMA is not able to identify translocations or noncontiguous insertions of the supernumerary PLP1 genes [abnormalities ; loci]. Because some CMA chips use large genomic fragments, false-positive or false-negative test results may occur, as with FISH analysis. One of the PCR-based methods should be used to verify the CMA results. See for laboratories offering CMA.

• Deletions of the entire PLP1 gene, which can be detected by FISH and by QPCR, occur in fewer than 2% of those with the Pelizeus-Merzbacher disease phenotype [Raskin et al 1991 ; Boespflug-Tanguy et al 1999 ; Inoue, Osaka et al 2002 ; Hobson, unpublished observations; Shaffer, unpublished observations]. Inoue, Osaka et al (2002) determined that the individual originally described with a PLP1 deletion has a complex rearrangement with both deletion of PLP1 and an inverted insertion of a more distal portion of the X chromosome at the deletion junction. In addition, this individual has duplication of a region 3' of PLP1 [Hobson, Ritterson et al 2002]. Partial PLP1 deletion has also been reported [Nave & Boespflug-Tanguy 1996].

• Position effect rearrangements appear to account for a small proportion of PMD and SPG2.

  • Disruption of regulatory elements of a gene neighboring PLP1 resulting in dysregulation of PLP1 expression through position effect was proposed as the explanation for a PMD-like syndrome in a child in whom conventional chromosome analysis identified an inversion of the X chromosome with a breakpoint near (70 kbp) but not including the PLP1 gene [Muncke et al 2004].
  • Position effect of a duplication identified by FISH that was near but not within the PLP1 gene has been invoked as the cause of the neurologic syndrome in a man with spastic paraplegia [Lee et al 2006].

Sequence analysis.  Point mutations, which account for approximately 15%-20% of identified PLP1 mutations, can be identified by gene sequencing [Pratt et al 1991 , Pratt et al 1992 , Sistermans et al 1998]. While most point mutations result in missense or frameshift changes, mutations that affect splicing also occur [Hobson et al 2000 , Hobson et al 2002 , Hübner et al 2005 , Hobson et al 2006 , Wang et al 2006].

Table 2 summarizes molecular genetic testing for this disorder.

Table 2. Molecular Genetic Testing Used in the PLP1-Related Disorders Test Method Mutations Detected Mutation Detection Frequency  1 Test Availability Duplication/deletion testing  2 Duplication/deletion of PLP1 50%-75% Clinical Sequence analysis Point mutations of PLP1 15%-25%  3

1. Proportion of affected individuals with a mutation(s) as classified by test method 2. Includes FISH, array genomic hybridization, Southern blot analysis, quantitative PCR, multiple ligation probe analysis (MLPA), multiplex amplifiable probe hybridization (MAPH), and real-time PCR 3. Percent of all those with a point mutation. Sequence analysis is generally only performed when a PLP1 duplication is not detected.

Interpretation of test results

• For issues to consider in interpretation of sequence analysis results, click here .
• It should be stressed that guidelines for the techniques used in duplication analysis are still under development, and equivocal or negative results from quantitative PCR or FISH should be interpreted with caution.

Testing Strategy

1. It is recommended that testing start with screening for PLP1 gene duplication, the most common type of mutation observed in males with PMD. Interphase FISH as well as quantitative PCR techniques are recommended.
   • Quantitative PCR and related techniques have the advantage of being able to detect duplications too close together to resolve by FISH, but the disadvantage of not being able to distinguish the more common tandem duplications from the less common duplications with distant insertions.
   • Metaphase FISH can identify distantly inserted duplications, whereas PCR cannot identify the location of the duplicated region.
   • Metaphase FISH can also demonstrate mosaicism for chromosomal anomalies, as in the unusual situation in which a woman was mosaic for both duplication and deletion of PLP1 and therefore had normal quantitative PCR [Woodward et al 2003].
2. When appropriate, karyotype analysis should be performed to evaluate an affected male for the presence of two X chromosomes (Klinefelter syndrome) or to identify individuals who have X-chromosome rearrangements that may cause position effect-related disturbance of PLP1 expression.
3. If a PLP1 duplication is not identified, sequencing of the PLP1 gene is the next step.

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutations in the PLP1 gene.

Clinical Description

Natural History

Pelizaeus-Merzbacher disease (PMD) and X-linked spastic paraplegia 2 (SPG2) are at opposite ends of a clinical spectrum of disease caused by mutations of the gene for proteolipid protein (PLP1), which results in defective central nervous system (CNS) myelination. PMD and SPG2 have been observed in different males within the same family [Bonneau et al 1993 , Hodes et al 1993 , Nave & Boespflug-Tanguy 1996 , Seitelberger et al 1996 , Sistermans et al 1998].

Connatal PMD, the most severe form, is apparent at birth or in the first few weeks of life. Findings include pendular nystagmus, hypotonia, pharyngeal weakness, and stridor. Seizures may develop in affected infants, and motor deficits are severe.

Later, children with connatal PMD may have short stature and poor weight gain. Hypotonia later evolves into spasticity of the extremities that is usually quite severe. Children do not walk or develop effective use of the upper limbs. Verbal expression is severely limited, but comprehension may be significant. Swallowing difficulties may require consideration of feeding tube placement.

Affected children may die during infancy or childhood, usually of aspiration; with attentive care, they may live into the third decade or longer.

Classic PMD was originally described by Pelizaeus (1885) and Merzbacher (1910). Males with classic PMD usually develop nystagmus, which may not be recognized until several months of age; in rare cases, nystagmus does not develop. Affected children have hypotonia and develop titubation (tremor of the head and neck), ataxia, and spastic quadriparesis beginning in the first five years. They usually have some purposeful voluntary control of the arms. If acquired, ambulation usually requires assistive devices such as crutches or a walker and is lost as spasticity increases during later childhood or adolescence.

Cognitive abilities are impaired, but exceed those of the more severely affected children; language and speech usually develop. Extrapyramidal abnormalities, such as dystonic posturing and athetosis, may occur.

Survival into the sixth or seventh decade has been observed.

A transitional form, intermediate in onset and severity to the connatal and classic forms of PMD, has also been defined.

PLP1 null syndrome is distinguished by the absence of nystagmus and the presence of relatively mild spastic quadriparesis that mostly affects the legs, with ataxia and mild multifocal demyelinating peripheral neuropathy. Those with the PLP1 null syndrome generally ambulate better than those with classic PMD but may progress more rapidly because of degeneration of axons, inferred on the basis of magnetic resonance spectroscopy, which demonstrates reduced levels of white matter NAA [Garbern et al 2002].

Complicated spastic paraparesis (SPG2) often includes autonomic dysfunction (such as spastic urinary bladder), ataxia, and nystagmus. A clear distinction cannot be drawn on objective criteria between complicated spastic paraplegia and relatively mild PMD (such as the PLP1 null syndrome).

Pure spastic paraparesis (SPG2) does not, by definition, include other significant CNS signs, although autonomic dysfunction, such as spastic urinary bladder, may also occur. Life span is normal.

Males with SPG2 have reproduced; males with the PMD phenotype have not.

Heterozygotes.   Women with a PLP1 gene mutation may or may not have symptoms. Several investigators have observed that in families with severely affected males, the heterozygous women are unlikely to have clinical manifestations of the PLP1-related disorders, whereas in families with mildly affected males, the heterozygous women are more likely to have symptoms [Hodes et al 1997 , Sivakumar et al 1999 , Hurst et al 2006]. Thus, an inverse relationship exists between the severity of manifestations in males and the likelihood of heterozygous females having neurologic signs. The risk of developing neurologic signs in heterozygous females is greatest in families in which affected males have a PLP1 null syndrome, followed by those in which affected males have an SPG2 syndrome [Hurst et al 2006]. The risk of developing neurologic signs is lowest with PLP1 duplication heterozygotes, who usually have favorably skewed X-chromosome inactivation [Woodward et al 2000].

The following explanation is offered:

• Alleles associated with a severe phenotype cause apoptosis (cell death) of oligodendrocytes (the cells that make myelin in the central nervous system) during early childhood. In heterozygous females, the oligodendrocytes that express the mutant PLP1 allele on the active X chromosome undergo apoptosis early in life but are replaced over time by oligodendrocytes that express the normal PLP1 allele on the active X chromosome. Thus, females who carry a severe PLP1 allele may develop neurologic signs because of skewed inactivation of the X chromosome with the normal PLP1 allele (as with other X-linked recessive disorders) or may have transient signs (while the oligodendrocytes expressing the mutant PLP1 are still present) from which they later recover — a phenomenon unique to PLP1-related disorders [Hodes et al 1995 , Inoue et al 2001].
• Alleles associated with a mild phenotype in males do not cause apoptosis of oligodendrocytes. In heterozygous females, abnormal oligodendrocytes persist and can cause neurologic signs [Sivakumar et al 1999].

Hurst et al (2006) analyzed families with SPG2 or PMD and provided statistical support for the inverse correlation between the severity of phenotypes in affected males and their heterozygous relatives. These observations have important implications for genetic counseling and are discussed in Risks to sibs of a male proband .

Manifesting heterozygotes are usually not index cases, but rather are identified in the course of evaluating the relatives of an affected male.

Genotype-Phenotype Correlations

Some genotype-phenotype correlations exist.

Most individuals with duplications have classic PMD; however, some are classified as having connatal PMD and may have three or more copies of the PLP1 locus [Wolf et al 2005]. Variation in the extent of duplication or location(s) of the breakpoints or reinsertion sites may account for clinical variability. Other possible causes of variability include the genetic background of the individual.

The most severe clinical syndromes are typically caused by missense mutations (especially nonconservative amino acid substitutions) and other point mutations of PLP1.

The milder spastic paraplegia syndrome is most often caused by conservative amino acid substitutions in presumably less critical regions of the protein. The locations of these mutations do not provide a clear correlation between amino acid position and clinical phenotype. However, mutations in the PLP1-specific portion of the gene tend to cause less severe syndromes [Cailloux et al 2000].

Although PMD has classically been regarded as a strictly central nervous system disorder, those with null PLP1 mutations including deletion of PLP1 [Raskind et al 1991], a frameshift mutation [Garbern et al 1997], and a missense mutation affecting the initiation codon [Sistermans et al 1996] do develop a relatively mild demyelinating peripheral neuropathy, demonstrating that myelin proteolipid protein (PLP) and/or DM20 (an alternatively spliced transcript; see following) does indeed function in the peripheral as well as central nervous systems. Furthermore, the null phenotype has less severe CNS signs than those seen with the more typical forms of PMD. The null phenotype is associated with length-dependent degeneration of major central motor and sensory tracts and reduced levels of N-acetyl aspartate in cerebral white matter.

PLP1 encodes two major alternatively spliced transcripts: myelin proteolipid protein (PLP), encoded by the full-length PLP1 gene; and DM20, which lacks the PLP1-specific domain that encodes residues 117-151. Peripheral neuropathy as well as a relatively mild CNS syndrome result from mutations that affect only the PLP1-specific region [Shy et al 2003]. The CNS syndrome can be milder than that observed in individuals with the null phenotype.

Penetrance

PLP1 mutations are believed to be completely penetrant in males. The complete conservation of amino acid sequence between rodent and human PLP suggests that variation from the normal sequence is detrimental.

Anticipation

Anticipation has not been reported for PLP1 mutations.

Nomenclature

Older terms for myelin proteolipid protein include: lipophilin, Folch-Lees protein, major myelin proteolipid and proteolipid protein 1.

Proteolipid protein 1 was previously called proteolipid protein. After discovery of a similar gene that is predominantly expressed in gut, numerical designation was added.

Prevalence

In the US, the prevalence of PMD in the population is estimated to be about 1/200,000 to 1/500,000.

In a survey of leukodystrophies in Germany, the incidence of PMD was about 0.13 per 100,000 live births [Heim et al 1997].

Seeman et al (2003) reported that in the Czech Republic PLP1 mutations were detected in one per 90,000 births. While this may reflect a situation particular to the Czech Republic, it suggests that the prevalence of PMD may be higher than is generally recognized.

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

Individuals with PLP1-related disorders are often initially diagnosed with cerebral palsy or static encephalopathy.

Pelizaeus-Merzbacher disease (PMD).  The characteristic nystagmus and MRI changes should suggest the diagnosis of PMD/SPG2 especially if family history is consistent with X-linked inheritance.

An autosomal recessive syndrome characterized by early-onset nystagmus, delayed motor milestones, ataxia, progressive spasticity, partial seizures, mild peripheral neuropathy, and diffuse leukodystrophy on MRI was found to be caused by mutations in the GJA12 gene that encodes connexin 46.6 [Uhlenberg et al 2004]. Mice that are deficient in connexin 47 (the murine homolog of human connexin 46.6) are viable, but mice deficient in both Cx47 and Cx32 have a fatal CNS leukodystrophy [Menichella et al 2003].

A PMD-like disease linked to Xq21 was described by Lazzarini et al (1997). It is not necessarily a leukodystrophy, as no MRIs of live affected individuals are available and pathologic analysis of an affected member of the family showed intact myelin.

Other leukodystrophies such as metachromatic leukodystrophy , X-linked adrenoleukodystrophy , Krabbe disease , and Canavan disease do not typically cause nystagmus, and the MRI usually shows a regional predilection of abnormality, e.g., occipital white matter in X-linked adrenoleukodystrophy and frontal white matter in metachromatic leukodystrophy [Aicardi 1993 , Barkovich et al 1997 , Kim et al 1997]. In these leukodystrophies, nerve conduction velocity (NCV) and evoked potentials are usually abnormal [Lewis & Sumner 1982].

Childhood ataxia with central nervous system hypomyelination/vanishing white matter disease (CACH/VWM) is characterized by ataxia, spasticity, and variable optic atrophy. The phenotypes range from a subacute infantile form (onset before age 1 year) to an early-childhood-onset form (onset age 1-5 years) to a late-childhood/juvenile-onset form (onset age 5-15 years) to an adult-onset form. In the early-onset forms, decline is usually rapid and followed quickly by death; in the later-onset forms, mental decline is usually slower and more mild. Chronic progressive decline can be exacerbated by rapid deterioration during febrile illnesses or following head trauma. The diagnosis of CACH/VWM is based on clinical findings, characteristic abnormalities on cranial MRI, and identifiable mutations in one of five causative genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) encoding the five subunits of the eucaryotic translation initiation factor, eIF2B [Leegwater et al 2001]. Inheritance is autosomal recessive.

Alexander disease is an autosomal dominant disease caused by mutation in the gene encoding glial fibrillary acidic protein. Affected individuals have developmental delay, progressive spasticity, cognitive impairment, and macrocephaly. MRI shows extensive T2-weighted hyperintensity especially in the frontal white matter, but with periventricular T1-weighted hyperintensity and T2-weighted hypointensity [van der Knaap et al 2001].

Infants with congenital muscular dystrophy with merosin deficiency have markedly increased T2 signal in the cerebral white matter. Severe weakness and hypotonia in the absence of nystagmus should direct the clinician toward consideration of myopathy [Mercuri et al 1995 , van der Knaap et al 1997].

A fatal X-linked syndrome with ataxia, blindness, deafness, and mental retardation linked to Xq21-q24 has been described. The MRI does not show a pattern of leukodystrophy [Kremer et al 1996]. Mutations in the PLP1 coding regions have been excluded.

Some children with Salla disease (free sialic acid storage disorders) may present with hypotonia, nystagmus, and delay of motor and cognitive abilities. Seizures are more common than in PMD, but children with Salla disease are more likely to show improvement. A broad range of clinical severity exists, with a syndrome characterized by permanent quadriparesis and failure to acquire speech that is usually fatal during childhood to a relatively mild form with delayed speech, delayed ambulation, mild mental retardation, and normal life expectancy. In severely affected children, MRI shows diffusely abnormal myelination with uniformly hyperintense white matter on T2-weighted images; in less severely affected children, myelination is delayed and occurs especially in the periventricular regions [Sonninen et al 1999].

PCWH, a syndrome with peripheral congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg-Hirschsprung disease, is caused by truncating mutations of the SOX10 gene [Touraine et al 2000 ; Inoue, Shilo et al 2002 ; Inoue et al 2004].

Spastic paraplegia 2 (SPG2).  Certain mutations of the L1 gene are responsible for L1 syndrome , the phenotype of which ranges from X-linked spastic paraplegia type 1 (SPG1), MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs) to X-linked hydrocephalus [Jouet et al 1994]. MRIs of individuals with these disorders may show enlarged ventricles or agenesis of the corpus callosum but not leukodystrophy.

Several other forms of autosomal dominant and autosomal recessive spastic paraplegia need to be considered in the differential diagnosis of SPG2 [Fink et al 1996] (see Hereditary Spastic Paraplegia Overview).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with a PLP1-related disorder, the following evaluations are recommended:

• Physical examination to determine extent and severity of respiratory and feeding difficulties, weakness, hypotonia, spasticity, scoliosis, ataxia, visual impairment, cognitive impairment, contractures, joint dislocations, and ambulation
• In infants and children, developmental assessment to determine capabilities and needs for cognitive, physical and other symptomatic therapies
• Brain MRI (more helpful ≥ age 9 months) to determine severity of myelination abnormalities; in older children and adults, magnetic resonance spectroscopy to ascertain axonal dysfunction
• Assessment of peripheral nerve function using NCV to identify individuals with the PLP1 null syndrome
• Family history to identify other affected or at-risk individuals

Treatment of Manifestations

A multidisciplinary team comprising specialists in neurology, physical medicine, orthopedics, pulmonary medicine, and gastroenterology is optimal for care.

Early attention to swallowing difficulties and airway protection, especially in the most severely affected individuals, is important. Those with severe dysphagia may require feeding by gastrostomy.

Seizures are usually restricted to individuals with the most severe (connatal) syndrome and may not always be associated with electroencephalographic evidence for epileptiform waveforms, although they generally respond to antiepileptic agents such as carbamazepine.

Spasticity management may include physical therapy and exercises, including regular stretching exercises. Antispasticity medications such as baclofen (including intrathecal administration), diazepam, and tizanidine may be helpful, especially in combination with physical therapy, exercise, orthotics, and other assistive devices. In advanced cases, surgery to release joint contractures may be required.

Proper wheelchair seating and physical therapy may help prevent scoliosis, which when severe may result in pulmonary compromise as well as discomfort, especially with position changes. With severe scoliosis, corrective surgery may be necessary to preserve pulmonary function.

Specialized schooling arrangements are typically necessary for children with PLP1-related disorders. Developmental assessments can accurately assess a child's capabilities, which may be greater than is apparent because of severe motor deficits. Electronic or other communication devices may facilitate communication especially in children with visual and auditory impairment.

Surveillance

Semiannual to annual neurologic and physical medicine evaluation is indicated to monitor developmental progress during childhood and to monitor and treat spasticity and orthopedic complications as needed.

Agents/Circumstances to Avoid

No specific agents or exposures are known to worsen or accelerate the disease.

High temperature, as with fever, may aggravate neurologic signs and symptoms, as occurs in individuals with multiple sclerosis (Uthoff phenomenon).

Therapies Under Investigation

Partial myelination of the CNS by donor oligodendrocytes has been demonstrated in research involving animal models of PMD [Duncan et al 1997 , Learish et al 1999]. This approach is not available for humans and is of uncertain benefit.

Pharmacologic agents that lower expression of PLP1 should be of theoretical benefit in individuals with extra copies of PLP1, and those with severe point mutations. Preclinical studies are underway to test drugs of this type.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

No controlled studies, either successful or unsuccessful, have been reported for therapy of PMD or SPG2.

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

Mode of Inheritance

The