Plp1 Disorders
Summary
Clinical characteristics.
PLP1 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. Intrafamilial variation of phenotypes can be observed, but the signs are usually fairly consistent within families. Heterozygous females may manifest mild-to-moderate signs of the disease.
Diagnosis/testing.
The diagnosis of a PLP1 disorder is established in a male proband by identification of a hemizygous pathogenic variant involving PLP1. The diagnosis of a PLP1 disorder is usually established in a female with neurologic signs, a family history of a PLP1 disorder, and a heterozygous pathogenic variant in PLP1 identified by molecular genetic testing.
Management.
Treatment of manifestations: A multidisciplinary team comprising specialists in neurology, physical medicine, orthopedics, pulmonary medicine, and gastroenterology is optimal for care. Treatment may include gastrostomy for individuals with severe dysphagia; antiepileptic drugs 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 for severe scoliosis. Specialized education and assessments are generally necessary, and assistive communication devices may be helpful.
Prevention of secondary complications: Proper wheelchair seating and physical therapy may help prevent scoliosis; speech and swallowing evaluations can identify patients who may need a feeding tube for safer and/or adequate nutrition and hydration.
Surveillance: Semiannual to annual neurologic and physical medicine evaluations during childhood to monitor developmental progress, spasticity, and orthopedic complications.
Genetic counseling.
PLP1 disorders are inherited in an X-linked manner. De novo pathogenic variants have been reported.
- If the mother has a PLP1 pathogenic variant, the chance of transmitting the variant in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant may manifest mild-to-moderate signs of the disorder. (PLP1 alleles that cause relatively mild neurologic signs in affected males are more likely to be associated with neurologic manifestations in heterozygous females.)
- Males with the PMD phenotype do not reproduce; males with SPG2 phenotype transmit the PLP1 pathogenic variant to all of their daughters and none of their sons.
Prenatal testing for a pregnancy at increased risk is possible if the PLP1 pathogenic variant in the family is known.
Diagnosis
Suggestive Findings
A PLP1 disorder should be suspected in an individual with the following clinical and imaging features.
Clinical features
- Infantile or early childhood onset of nystagmus, hypotonia, and cognitive impairment
- Progression to severe spasticity and ataxia
- Spastic paraparesis with or without CNS involvement
- Spastic urinary bladder
Imaging features
Magnetic resonance imaging (MRI) (T2-weighted or fluid-attenuated inversion recovery (FLAIR) scans):
- Diffusely increased T2 signal intensity in the white matter of the cerebral hemispheres, cerebellum, and brain stem, consistent with hypomyelination [Steenweg et al 2010].
- Slowly progressive volume loss in older children [Sarret et al 2016].Note: 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 [Barkovich 2005]. Absence of these early changes should raise the consideration for PMD or other hypomyelinating disorders.
- Hypomyelination of early myelinating structures (HEMS). Individuals with HEMS show hypomyelinated structures which normally myelinate early in development, such as optic radiation and brain stem, whereas other white matter structures are better myelinated [Kevelam et al 2015].
- Spastic paraplegia 2 (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 [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.
Establishing the Diagnosis
The diagnosis of a PLP1 disorder:
- Is established in a male proband by identification of a heterozygous pathogenic variant in PLP1 by molecular genetic testing (see Table 1);
- Is usually established in a female with neurologic signs, a family history of PLP1 disorder, and a heterozygous pathogenic variant in PLP1 identified by molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (targeted deletion/duplication analysis, single-gene testing, multigene panel), and comprehensive genomic testing (exome sequencing, exome array, genome sequencing), depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of PLP1 disorders is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with hypotonia, cognitive impairment, and/or spastic paraparesis are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of a PLP1 disorder, molecular genetic testing approaches can include targeted deletion/duplication analysis, single-gene testing, or use of a multigene panel:
- Targeted deletion/duplication analysis. Multiplex ligation-dependent probe amplification (MLPA), targeted microarray, quantitative PCR (qPCR), or FISH analysis should be considered first to identify a PLP1 deletion/duplication.
- Single-gene testing. If a deletion/duplication is not identified, PLP1 sequence analysis should be considered. Sequence analysis of PLP1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants.Note: In individuals with HEMS, sequence analysis of intron 3 should be performed if no pathogenic variant is identified in exon 3B.
- A multigene panel that includes PLP1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by motor and cognitive impairment, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in PLP1 Disorders
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| PLP1 | Gene-targeted deletion/duplication analysis 3 | 60-70% 4, 5, 6 |
| Sequence analysis 7, 8 | 30%-40% | |
| See footnote 9 | <1% |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include multiplex ligation-dependent probe amplification (MLPA), a gene-targeted microarray, quantitative PCR, and long-range PCR designed to detect single-exon deletions or duplications.
- 4.
The majority of gene dosage changes are tandem duplications occurring in Xq22, which include all of PLP1. In rare instances, the duplicated region can be inserted at some distance from Xq22; four insertions have been reported: at Xp22, Xq28 [Woodward et al 1998, Hodes et al 2000], and 19qtel [Inoue et al 2002]; and in the Y chromosome [Woodward et al 2005]. Triplication, partial triplication, and quintuplication of PLP1 also occur [Boespflug-Tanguy et al 1994, Woodward et al 1998, Wolf et al 2005, Combes et al 2006]. In simplex females, PLP1 duplication often occurs with complex chromosomal rearrangements.
- 5.
Whole-gene deletions of PLP1 occur in fewer than 2% of those with the Pelizaeus-Merzbacher disease phenotype [Raskind et al 1991; Boespflug-Tanguy et al 1994; Inoue et al 2002; Shaffer, unpublished observations]. Inoue et al [2002] determined that the individual originally described with a PLP1 deletion has a complex rearrangement with both a 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 distal of PLP1 [Hobson et al 2002, Lee et al 2007]. Partial PLP1 deletion has also been reported [Combes et al 2006].
- 6.
Depending on the method used, larger deletion or duplication events may be detected. Position effect of a duplication identified by FISH that was near but did not include PLP1 has been invoked as the cause of the neurologic syndrome in a man with spastic paraplegia [Lee et al 2006].
- 7.
Sequence analysis which should include analysis of intron 3B detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 8.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- 9.
An inversion of the X chromosome with a breakpoint 70 kbp upstream of PLP1, identified by chromosome analysis, was proposed to disrupt PLP1 expression through position effect in a child with PMD-like syndrome [Muncke et al 2004].
Clinical Characteristics
Clinical Description
Males
Pelizaeus-Merzbacher disease (PMD) and X-linked spastic paraplegia 2 (SPG2) are at opposite ends of a clinical spectrum of disease caused by pathogenic variants in PLP1, which results in defective central nervous system (CNS) myelination. PMD and SPG2 have been observed in different males within the same family [Hodes et al 1993, Sistermans et al 1998].
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 2).
Table 2.
Spectrum of PLP1 Disorders
| Phenotype | Age of Onset | Neurologic Findings | Ambulation | Speech | Age at Death |
|---|---|---|---|---|---|
| Severe "connatal" PMD | Neonatal period | Nystagmus at birth; pharyngeal weakness; stridor; hypotonia; severe spasticity; ± seizures; cognitive impairment | Never achieved | Absent, but nonverbal communication & speech comprehension possible | Infancy to 3rd decade |
| Classic PMD | 1st 5 yrs | Nystagmus in 1st 2 mos; initial hypotonia; spastic quadriparesis; ataxia titubation; ± dystonia, athetosis; cognitive impairment | W/assistance if achieved; lost in childhood/ adolescence | Usually present | 3rd-7th decade |
| PLP1 null syndrome | 1st 5 yrs | No nystagmus; mild spastic quadriparesis; ataxia; peripheral neuropathy; mild-to-moderate cognitive impairment | Present | Present; usually worsens after adolescence | 5th-7th decade |
| Complicated SPG (SPG2) & HEMS | 1st 5 yrs | Nystagmus; ataxia; autonomic dysfunction 1; spastic gait; little or no cognitive impairment | Present | Present | 4th-7th decade |
| Uncomplicated SPG (SPG2) | Usually 1st 5 yrs; may be 3rd-4th decade | Autonomic dysfunction 1; spastic gait; normal cognition | Present | Present | Normal |
HEMS = hypomyelination of early myelinating structures; PMD = Pelizaeus-Merzbacher disease; SPG = spastic paraplegia
- 1.
Spastic urinary bladder
Severe or "connatal" PMD is apparent at birth or in the first few weeks of life. Findings include pendular nystagmus, hypotonia, and stridor. Seizures may develop in affected infants, and motor deficits are severe (e.g., infants do not gain head control).
Later, children with severe 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 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. 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; ambulation is generally 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 N-acetyl aspartate [Garbern et al 2002].
Complicated spastic paraparesis (SPG2) and hypomyelination of early myelinating structures (HEMS) often include autonomic dysfunction (e.g., spastic urinary bladder), ataxia, and nystagmus. A clear distinction cannot be drawn on objective criteria between complicated spastic paraplegia and relatively mild PMD (e.g., 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.
Neurophysiologic Studies
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.
Except in families with PLP1 null alleles or pathogenic variants affecting the PLP1-specific region or some splice site variants [Shy et al 2003, Vaurs-Barrière et al 2003], peripheral nerve conduction studies are normal. When peripheral neuropathy is present, it is mild in comparison to the CNS 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.
Heterozygous Females
Women with a PLP1 pathogenic variant 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 a PLP1 disorder, whereas in families with mildly affected males, the heterozygous women are more likely to have symptoms [Keogh et al 2017]. Thus, an inverse relationship exists between the severity of manifestations in males and the likelihood of heterozygous females having neurologic signs.
The risk to heterozygous females of developing neurologic signs is greatest in families in which affected males have a PLP1 null syndrome, followed by those in which affected males have an SPG2 syndrome or HEMS [Hurst et al 2006]. The risk of developing neurologic signs is lowest in heterozygous females with a PLP1 duplication, 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 CNS) during early childhood. In heterozygous females, the oligodendrocytes that express the mutated 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 pathogenic variant 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 mutated PLP1 are still present) that abate as the degenerating oligodendrocytes are replaced by those expressing the normal PLP1 allele [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 Risk to Family Members, 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.
Females with PMD have been described. This is thought to be due to unfavorable X inactivation in the brain [Scala et al 2019]. In some, there was considerable improvement of signs and symptoms after infancy. One female with classic PMD was found to have an insertion of an extra copy of PLP1 at chromosome 1p36 [Masliah-Planchon et al 2015]. Additional complex chromosome rearrangements in females with PMD have been described [Ida et al 2003, Yiu et al 2009].
Genotype-Phenotype Correlations
Some genotype-phenotype correlations exist.
Most individuals with PLP1 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.
The most severe clinical syndromes are typically caused by missense variants (especially nonconservative amino acid substitutions) and other PLP1 single-nucleotide variants or indels.
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 pathogenic variants do not provide a clear correlation between amino acid position and clinical phenotype. However, pathogenic variants in the PLP1-specific domain encoded by amino acid residues 117-151 and in intron 3 tend to cause less severe syndromes [Cailloux et al 2000, Taube et al 2014, Kevelam et al 2015] (see Molecular Genetics).
Although PMD has classically been regarded as a strictly CNS disorder, those with null PLP1 variants, including deletion of PLP1 [Raskind et al 1991], a frameshift variant, and a missense variant affecting the initiation codon do develop a relatively mild demyelinating peripheral neuropathy, demonstrating that myelin proteolipid protein (PLP1) and/or DM20 (an alternatively spliced transcript; see following paragraph and Molecular Genetics) does indeed function in the peripheral nervous system as well as in the CNS. 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.
Peripheral neuropathy as well as a relatively mild CNS syndrome results from pathogenic variants that affect only the PLP1-specific region [Shy et al 2003] (see Molecular Genetics). The CNS syndrome can be milder than that observed in individuals with the null phenotype.
Penetrance
PLP1 pathogenic variants are believed to be completely penetrant in males.
Nomenclature
Pelizaeus-Merzbacher disease is also known as sudanophilic or orthochromatic leukodystrophy.
Proteolipid protein 1 was previously called proteolipid protein. After discovery of a similar gene that is predominantly expressed in gut, numerical designation was added.
Note also that the older literature usually begins numbering of the amino acids with the glycine encoded by codon 2, since the initiation methionine is cleaved post-translationally.
Prevalence
In the US, the prevalence of PMD in the population is estimated at 1:200,000 to 1:500,000.
In a survey of leukodystrophies in Germany, the incidence of PMD was approximately 0.13:100,000 live births [Heim et al 1997].
Seeman et al [2003] reported that in the Czech Republic PLP1 pathogenic variants were detected in 1:90,000 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
Individuals with PLP1 disorders are often initially diagnosed with cerebral palsy or static encephalopathy.
Pelizaeus-Merzbacher Disease (PMD)
The combination of nystagmus within the first two years of life, initial hypotonia, and abnormal white matter changes on the brain MRI (e.g., abnormal signal in the posterior limbs of the internal capsule, the middle, and superior cerebellar peduncles and the medial and lateral lemnisci, all of which should be myelinated in a normal newborn) should suggest the diagnosis of PMD, especially if the family history is consistent with an X-linked disorder. In a recent survey of children with inherited diseases of white matter identified by neuroimaging, 7.4% had PMD, the second most common cause of leukodystrophy [Bonkowsky et al 2010], suggesting that the disease is relatively common.
Approximately 20% of males with clinical findings consistent with a PLP1 disorder do not have identifiable pathogenic variants in PLP1. Pathogenic variants in additional genes have been identified in individuals with a PMD-like phenotype and hypomyelination on brain MRI (see Table 3).
Hypomyelination occurs in several disorders with clinical phenotypes distinct from PMD. 4H leukodystrophy is the most frequent hypomyelinating disorder after PMD, individuals with 4H leukodystrophy usually do not have nystagmus, ataxia is prominent, and spasticity is mild or not present [Wolf et al 2014]. Oculodentodigital dysplasia presents sometimes in adulthood, with a SPG-like phenotype; nystagmus is usually not present [Harting et al 2019]. (For MRI characteristics and differential diagnosis of hypomyelination see also Steenweg et al [2010] and van der Knaap et al [2019]).
Table 3.
Genes of Interest in the Differential Diagnosis of Pelizaeus-Merzbacher Disease (PMD)
| Gene(s) 1 | Disorder 2 | MOI | Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/PMD | Distinguishing from PMD | |||
| AIFM1 | Hypomyelination w/spondyloepiphyseal dysplasia 3 | XL | Hypomyelination | Spondyloepiphyseal dysplasia |
| DARS1 | Hypomyelination w/brain stem & spinal cord involvement & severe leg spasticity (OMIM 615281) | AR | Spasticity/ataxia; nystagmus; hypomyelination | Characteristic involvement of brain stem & spinal cord structures on MRI |
| EPRS1 | Hypomyelinating leukodystrophy 15 (OMIM 617951) | AR | Spasticity/ataxia; nystagmus; hypomyelination | Posterior columns may be affected on MRI |
| FAM126A | Hypomyelination & congenital cataract | AR | Spasticity/ataxia; nystagmus; demyelinating peripheral neuropathy; hypomyelination | Congenital cataract; areas w/both T2-weighted hyperintensity & T1-weighted hypointensity |
| GJA1 | Oculodentodigital dysplasia (OMIM 164200) | AD | Hypomyelination | Mild symptoms, sometimes diagnosis only in adulthood; syndactyly; ocular abnormalities; dysmorphic signs; prominent spastic bladder |
| GJC2 | Pelizaeus-Merzbacher-like disease 1 | AR | Spasticity/ataxia; nystagmus; hypomyelination | Epilepsy is frequent. More pronounced hypomyelination in subcortical white matter; prominent brain stem involvement |
| HSPD1 | Hypomyelinating leukodystrophy 4 (OMIM 612233) | AR | Resembles severe PMD 4; hypomyelination | Acquired microcephaly; severe epilepsy |
| NKX6-2 | NKX6-2 disorder | AR | Spasticity/ataxia; nystagmus; hypotonia; hypomyelination | Severe early dystonia, early-onset (transitory) respiratory failure |
| POLR3A POLR3B POLR3K POLR1C | 4H leukodystrophy (hypomyelination, hypodontia, & hypogonadotropic hypogonadism) | AR | Ataxia; hypomyelination | Myopia (no nystagmus); hypodontia; hypogonadotropic hypogonadism; early cerebellar atrophy; better myelination of posterior limb of the internal capsule, ventrolateral thalamus & optic radiation |
| RARS1 | Hypomyelinating leukodystrophy 9 (OMIM 616140) | AR | Spasticity/ataxia; nystagmus; hypomyelination | No specific distinguishing features; in severe cases, microcephaly & early epileptic encephalopathy |
| SLC16A2 | Allan-Hernon-Dudley syndrome (MCT8-specific thyroid hormone cell-membrane transporter deficiency) | XL | Neonatal hypotonia, nystagmus, severe DD | High serum T3 concentration; low serum reverse T3 concentration; MRI shows (severely) delayed myelination, but not hypomyelination |
| SLC17A5 | Salla disease (see Free Sialic Acid Storage Disorders) | AR | ||