Pelizaeus–Merzbacher Disease

Pelizaeus–Merzbacher disease (PMD, OMIM 312080) is the prototypic hypomyelinating disorder, and is caused by alterations in the proteolipid 1 (PLP1) gene [Hudson et al., 1989; Trofatter et al., 1989]. Located on Xq22.2, this gene encodes the PLP1 protein, which constitutes roughly half of all myelin protein. The most common abnormality is a duplication of the entire gene, found in 60–70 percent of PMD cases and associated with the classic form of the disease [Ellis and Malcolm, 1994; Sistermans et al., 1998]. The lack of common breakpoints in these duplications results in varying sizes of the duplicated area between patients. Missense mutations account for 10–15 percent of cases. Several missense mutations affecting splicing or putative regulation of expression have also been described. Deletions are also seen in a smaller number of cases. Triplications are present in 1–2 percent of cases; higher copy numbers have been described in one child. More complex chromosomal rearrangements involving PLP1 or its promoter region have been described in individual cases [Muncke et al., 2004]. Deletions or null mutations are rare. Roughly 15 percent of cases fulfilling diagnostic criteria for PMD do not possess identifiable PLP1 mutations, suggesting the possibility of mutations in regulatory regions beyond genetic assays.

The clinical features of PMD were well described by Pelizaeus and Merzbacher. Typically, affected boys develop a pendular nystagmus at the age of several weeks, similar to infants with congenital nystagmus. Shortly thereafter, delayed psychomotor development becomes apparent. These infants show axial hypotonia with difficult head control, titubation, exaggerated tendon reflexes, and a combination of ataxia and extrapyramidal features. Nystagmus may improve or even disappear over time. Optic atrophy is common. In classic PMD, patients are unable to walk, and often unable to sit without support. If they develop active speech, it is difficult to understand because of dysarthria and scanning speech. A learning problem or cognitive impairment is common, although motor impairment tends to be more pronounced than cognitive disability. In connatal PMD, symptoms are evident shortly after birth and often include congenital stridor, feeding difficulties, and profound hypotonia. Development is more impaired than in the classic form; connatal PMD patients do not learn to talk or sit without support, and make very little developmental progress. Microcephaly is common. Transitional PMD is intermediate in severity between the connatal and classic variants. These three subtypes likely form a continuous spectrum. Epilepsy is rare in PMD, even in the severe connatal form, and has only been described in exceptional cases.

Clinical course in PMD is chronic. Until late childhood or early adolescence, patients may improve and make definite, albeit slow, developmental progress. From this age, however, slow deterioration begins, with insidious progression of neurologic symptoms and slow cognitive decline. Optic atrophy, if not yet present, develops. While difficult to predict for individual patients, life expectancy is reduced, and depends on severity of neurologic deficits and additional complications. Connatal PMD patients often die within the first decade of life, classic PMD patients in the second or third decade.

PMD is allelic with a relatively mild disorder, X-linked spastic paraplegia type 2 (SPG2), also caused by PLP1 mutations [Saugier-Veber et al., 1994]. In its pure form, the sole symptom associated with SPG2 is slowly increasing spasticity, more of the legs than of the arms, which begins during childhood or adolescence. In the complicated forms, additional symptoms, such as nystagmus, ataxia, dysarthria, and mild cognitive impairment, are present. Life expectancy in this form is normal. Peripheral neuropathy is another possible finding with certain PLP1 mutations. Altogether, alterations of PLP1 mutations give rise to a spectrum of disorders, ranging from the very severe connatal phenotype to mild spastic paraplegia with adolescent onset.

Genotype–phenotype correlations have been established for most PLP1 alterations, although clinical heterogeneity among patients with common genetic alterations makes definitive characterization difficult. Symptoms do not correlate with duplication size, but high copy number appears to predict increased clinical severity. Severe epilepsy has been reported in children with triplications, an otherwise uncommon feature of PMD [Wolf et al., 2005]. Point mutations are associated with the full spectrum of PLP1-connected disorders [Cailloux et al., 2000]. Demyelinating neuropathy is associated with either null mutations or mutations in PLP-specific regions. Patients with functional null mutations show relatively mild clinical course; they usually achieve independent, albeit clumsy, ambulation, and show mild cognitive impairment and demyelinating neuropathy. As spasticity increases after the first decade, patients become wheelchair-bound and develop pseudobulbar palsy. Histopathologic investigations show evidence of length-dependent axonal degeneration in these patients and in corresponding mouse models [Garbern et al., 2002].

PLP1 is a highly conserved, hydrophobic membrane protein with four transmembrane domains and a large cytosolic loop between the second and third transmembrane domains. The N- and C-termini are located in the cytoplasm. Different splicing of PLP1 yields a second, smaller isoform, DM20. Both isoforms are primarily expressed within the CNS. While the function of PLP1 and DM20 remains poorly understood, mutations that leave DM20 intact are associated with relatively mild phenotype. Mutations associated with severe phenotype likely cause protein misfolding, which activates compensatory oligodendrocytic responses that ultimately cause oligodendrocyte apoptosis. The pathogenicity of PLP1 duplications is less well understood, although it has been speculated that overexpressed PLP1 in endosomal and lysosomal compartments depletes myelin rafts of lipids necessary for the production of functional myelin compounds [Garbern, 2007].

Interestingly, female heterozygotes may develop symptoms. In cases of PLP1 duplications, symptoms are rare and include transient, PMD-like symptoms in young girls. Symptom development in females tends to be associated with mutations causing mild phenotypes in males. It has been suggested that severe mutations and duplications cause early apoptosis in oligodendrocytes expressing the mutated allele in females. Oligodendrocytes expressing the wild-type allele proliferate to compensate for the loss of mutant cells. Mild mutations, however, do not elicit oligodendrocytic apoptosis, and surviving mutant cells cause impaired myelin formation and ultimate axonal degeneration. Female carriers of these mutations develop slowly progressive spastic paraplegia and cognitive decline later in life.

MRI in PMD shows hypomyelination, indicated by diffusely elevated white-matter signal on T2 (Figure 71-3A). Myelination is arrested and fails to progress on repeated scans. Some patients show a more mottled, “tigroid” signal, perhaps due to small myelinated areas surrounding blood vessels. In some patients, myelin deposition is seen in the posterior limb of the internal capsule or the optic radiations. Myelination is usually present in the brainstem and sometimes in the cerebellar hemispheres. Often – but not always – the pyramidal tracts in the brainstem show high T2 signal. At a young age, atrophy is not considerable, especially in the cerebellum, although white-matter volume may be decreased. The corpus callosum is thin, reflecting lack of myelinated axons. As children grow older, generalized atrophy develops. Proton MR spectroscopy reveals low choline, due to reduced membrane turnover in the absence of myelinating oligodendrocytes, and normal to elevated N-acetylaspartate (NAA), due to more densely packed axons. Patients with null mutations or deletions show more advanced supratentorial myelination. In SPG2 patients, MRI abnormalities are variable, ranging from diffuse mild hypomyelination to mild periventricular signal changes. Carrier females sometimes display small areas of elevated white-matter signal, but MRI is usually normal.

Diagnosis of PMD is based on typical clinical presentation, radiologic evidence of hypomyelination, and detection of PLP1 alterations. Routine laboratory and metabolic tests, including cerebrospinal fluid (CSF), are normal. As most PLP1 alterations are duplications, simple sequencing must also be accompanied by gene dose quantification by Southern blot, quantitative polymerase chain reaction (PCR), or, more recently, multiple ligation-dependent probe amplification (MLPA). Recently, elevation of the dipeptide N-acetylaspartylglutamate (NAAG) has been described in several PMD cases, with NAAG level appearing to predict clinical severity [Burlina et al., 2006]. The mechanism of NAAG elevation, however, remains unknown, and it is neither specific to PMD, nor a marker of hypomyelination.

Pelizaeus–Merzbacher-Like Disease

Pelizaeus-Merzbacher-like disease (PMLD, OMIM 608804) is phenotypically similar to PMD, although its inheritance is autosomal-recessive instead of X-linked. Children with hypomyelination on MRI, but without the PMD phenotype, are often mischaracterized as PMLD. The primary clinical features include early nystagmus, ataxia, and spasticity.

PMLD is a genetically heterogeneous disease. In most cases, no gene has been identified. In a small subset of PMLD patients (fewer than 10 percent), mutations in GJC2 (also called GJA12), coding for connexin 46.6 (Cx47), have been found (OMIM 608804) [Henneke et al., 2008]. Located on chromosome 1q41–q42, this gene was identified using a homozygosity mapping approach in a large consanguineous family [Uhlenberg et al., 2004]. Mutations were subsequently found in other, unrelated, patients, confirming GJC2 as the responsible gene. It remains the only gene identified in PMLD; other approaches to identify PMLD genes, such as sequencing candidate genes for structural myelin proteins, have so far been unsuccessful.

Connexins (Cx) are integral to intercellular junctions. In the CNS, there are gap junctions that are an essential component of the large glial syncytium among astrocytes and oligodendrocytes. Oligodendrocytes express two connexins, Cx32 and Cx47, and GJC2 mutations cause loss of Cx47 function, disturbing gap-junction properties between oligodendrocytes and astrocytes. The mechanistic link between these molecular genetic insults and hypomyelinating phenotype remains unclear. Interestingly, other connexin genes have been implicated in white-matter disorders. GJA1 (Cx43) mutations are associated with oculodentodigital dysplasia, which is also characterized by hypomyelination. GJB1 (Cx32) mutations lead to Charcot–Marie–Tooth disease type I. Transient, sometimes fluctuating, central neurological symptoms may occur in this disorder, often associated with mild infections. MRI reveals mild cerebral white-matter hyperintensities, likely reflecting myelin splitting and intramyelinic oedema.

As in PMD, patients typically present with nystagmus apparent after the first few weeks of life. Motor development is delayed and children display ataxia during the first few years. Pyramidal signs and frank spasticity often develop later. Compared with boys with classic PMD, motor and cognitive performance in PMLD is better, especially during the first years of life, and children are often able to walk, some without support. However, patients show a more precipitous decline, with progressive spasticity, prominent pseudobulbar signs, and facial weakness reminiscent of myopathic face. Patients become wheelchair-bound in their teens. Epilepsy starting in late school age has been reported in a substantial proportion of cases, and may be more severe in isolated cases, a very unusual feature for boys with PMD. Mild demyelinating peripheral neuropathy revealed by nerve conduction studies has been described in some patients, although it does not influence the overall clinical manifestation. A recently described family carrying a homozygote missense mutation in GJC2 showed a phenotype of almost pure spastic paraplegia and minor cerebellar signs [Orthmann-Murphy et al., 2008]. There are no histopathological data on PMLD.

MRI shows hypomyelination, and prominent signal abnormalities of the pyramidal tract of the brainstem have been described (Figure 71-3B). Cerebellar atrophy is mild or absent, at least in the early stages; supratentorial atrophy with considerable white-matter loss is prominent in older patients [Wolf et al., 2007]. Brainstem atrophy is often seen in later stages. Routine metabolic investigations are normal. In CSF, NAAG is elevated, as it is in PMD [Sartori et al., 2008].

4H Syndrome

This recently described leukoencephalopathy (OMIM 612440) is also characterized by hypomyelination. Its name is derived from its three main clinical findings: hypomyelination, hypodontia, and hypogonadotropic hypogonadism [Wolf et al., 2005, 2007; Timmons et al., 2006]. The disorder is rare and a genetic locus has not yet been identified. As affected siblings of both sexes have been reported, inheritance is presumed to be autosomal-recessive.

Initial development is normal, and affected children often start to walk without support before 18 months. Their gait, however, does not improve, as in healthy children, and by the age of 2–3 years, parents note that their children walk clumsily and frequently fall. Fine motor skills are also poor. Neurologic examination reveals pronounced ataxic gait, mild intention tremor, and dysmetria. Cerebellar eye movement disorder with saccadic pursuit and gaze-evoked nystagmus is seen. Clinical course remains more or less stable, although many parents describe episodic deterioration with infections. Ataxia progresses towards the end of the first decade, and pyramidal signs develop. Children lose independent ambulation, and are ultimately almost unable to move, despite largely intact cognitive function. A considerable spectrum of severity exists; some children never gain independent ambulation, while others develop into adulthood with only minor ataxia. Cognition is less impaired than motor skills, as often seen in pediatric white-matter disorders, but is not normal. Most children show mild to moderate learning disability. Many have a language disorder with dysarthria. Peripheral neuropathy is an inconstant finding.

Besides these neurological symptoms, hypodontia is the most prominent diagnostic sign (Figure 71-4). Eruption of deciduous teeth is delayed, and its order disturbed. Normally, the lower median deciduous incisors erupt first, followed by the upper median incisors. In 4H syndrome, the deciduous molars erupt first, followed by the incisors, and finally by the upper median incisors. Despite this delayed and disorganized eruption, the deciduous teeth are usually complete. In the permanent dentition, however, some teeth are missing. The incisors have an abnormal shape and often also a yellowish color. About 10 percent of patients show natal teeth, an otherwise very rare finding occurring only in 1 in 1000–3000 newborns.

Fig. 71-4 Dental phenotype of children with 4H syndrome.

The upper median incisors erupt late. A, Child aged 5 years. The typical situation in a younger child with lacking upper median (and in this case also lateral) incisors. The left lower median incisor [Schiffmann et al., 1994] has not erupted yet. B, Child aged 8 years. No deciduous incisors have erupted. The right permanent upper median incisor [Paznekas et al., 2003] shows yellowish discoloration. The left median incisors have not erupted yet.

Hypogonadotropic hypogonadism can only be diagnosed in adolescence when patients fail to enter puberty. Low luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels indicate central hypogonadism, although the cause of reduced LH and FSH is unknown. Other common symptoms include myopia, which may be high, and small stature, which becomes evident around school age.

As the name of the disease suggests, MRI shows hypomyelinated white matter (see Figure 71-3C). T2 signal in the supratentorial white matter is diffusely elevated, with the exception of aspects of the posterior limb of the internal capsule and optic radiation. T1 white-matter signal varies from hypointense to hyperintense, depending on the amount of myelin deposited. Cerebellar white matter is usually myelinated on T2. Corpus callosum is thin. There is also early and considerable cerebellar atrophy, more of the vermis than of the hemispheres, in virtually all patients. Whether clinical severity correlates with amount of myelin deposited or degree of initial cerebellar atrophy has not yet been elucidated. Proton MR spectroscopy reveals low choline, as is usual in hypomyelination, and often also elevation of myo-inositol compatible with gliosis. In the later stages, considerable cortical atrophy and white-matter loss develop, indicating on-going myelin loss.

Metabolic investigations are all normal. In some children, a muscle biopsy, with assessment of respiratory chain enzymes, has been performed in the context of deterioration of symptoms with infections, but showed normal results. Analysis of the known genes involved in hypomyelination, including GJA1, in which mutations lead to oculodentodigital dysplasia, did not reveal abnormalities [Wolf et al., 2007].

Oculodentodigital Dysplasia

Oculodentodigital dysplasia (ODDD, OMIM 164200) is another hypomyelinating disorder characterized by dental abnormalities. Its inheritance is autosomal-dominant. Dominant mutations in another connexin gene on chromosome 6q21–23.2, GJA1, coding for connexin 43 (Cx43), cause ODDD. There is one family described with autosomal-recessive mutations leading to the same phenotype. Cx43 is expressed in the developing brain and teeth, and also in hands and feet [Paznekas et al., 2003].

ODDD is likely not as common as 4H syndrome. Affected children are usually regarded as neurologically normal, and are primarily diagnosed based on the typical dysmorphic signs. These consist of ocular anomalies (microphthalmus, microcornea, iris abnormalities, short palpebral fissures, epicanthus), facial dysmorphic signs (especially a thin nose with hypoplastic alae, small anteverted nares, and a prominent columella), hand and foot abnormalities (syndactyly of third, fourth, and fifth fingers and second, third, and fourth toes, clinodactyly of fifth fingers), thin and brittle hair, and sometimes microcephaly. Dental abnormalities have not been described in detail but are present in all patients. Teeth are brittle and prone to decay. They show early discoloration, probably due to a defect in dentine. Microdontia and hypodontia are other common findings.

Neurologic symptoms are common, although no large case series has been reported, so little is known about the exact time course and development of neurologic abnormalities. In childhood and adolescence, coordination problems and mild ataxia are common. In adulthood, slow neurologic deterioration is seen, with development of pyramidal tract lesions, ataxia, dysarthria, loss of bladder control, and finally, frank spasticity. Unsupported gait may become impossible in late stages. Optic atrophy and deafness are possible. Cognition is preserved in most patients, although learning disabilities have been reported. Whether and to what extent early cognitive deterioration occurs awaits further study. Peripheral nervous system appears unaffected [Loddenkemper et al., 2002].

MRI shows mild to moderate hypomyelination, supratentorial atrophy, and mild cerebellar atrophy. Some authors describe hypointense signal of the basal ganglia and thalami.

Hypomyelination with Congenital Cataract

Hypomyelination with congenital cataract (HCC, OMIM 610532) is a recently described disorder with CNS hypomyelination, reported in five families. The genetic locus of HCC is FAM126A, earlier called DRCTNNB1A, on chromosome 7p15.3. It encodes the Hyccin membrane protein. Missense mutations, mutations affecting splice sites, and a deletion of the entire gene have been identified, but the gene’s role in myelination remains obscure.

Affected patients present early with delayed motor development. Cognitive development is mildly to moderately delayed. Most HCC children learn to walk with support before their second birthday. Neurological examination reveals dysarthria, moderate to severe spasticity with elevated muscle tone, brisk reflexes, extensor plantar response, and cerebellar signs such as intention tremor and dysmetria. Nystagmus is rare. As in other hypomyelinating disorders, progression of secondary neurologic symptoms occurs, and children may be unable to walk, even with support, by the end of the first decade. An additional pathognomonic finding is congenital cataract [Zara et al., 2006]. Several HCC cases have been published, and one patient failed to develop cataract until age 9. A small subset of HCC patients suffers from occasional seizures. Peripheral neuropathy is seen in almost all patients, leading to loss of previously exaggerated tendon reflexes and distal muscle wasting. It is not yet known whether a broad phenotypic spectrum exists in HCC, and clinical presentation is heretofore remarkably homogeneous, with the exception of cataract and peripheral neuropathy, which are not present in all patients. There are no data yet about CNS pathology, nor experimental models to elucidate Hyccin function.

Electrophysiological studies show evidence of demyelinating neuropathy. Sural nerve biopsy in several patients revealed lack of myelinated nerve fibres, thin, noncompacted myelin surrounding the few myelinated axons, and, in some cases, formation of small onion bulbs near Schwann cell processes.

MRI shows hypomyelination, as evident from the diffusely elevated T2 white-matter signal. In contrast to those with other hypomyelinating disorders, HCC patients show additional areas of higher T2 white-matter signal and decreased signal intensity on corresponding T1-weighted images, indicating elevated water content in these areas, particularly in periventricular regions [Rossi et al., 2007] (Figure 71-3E). Cerebellar atrophy is not seen. In the early stages, normal myelin signal may be apparent in subcortical fibres and corpus callosum. In the late stages, white matter appears shrunken, with increased apparent diffusion quotients. Proton MR spectroscopy gives variable results, depending on the disease stage. Choline may even be slightly elevated in the early stages, which is unusual for a hypomyelinating disorder, and decreased in later stages.

Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum

Hypomyelination with atrophy of the basal ganglia and cerebellum (HABC, OMIM 612438) is a rare disorder of unknown genetic origin [van der Knaap et al., 2002]. As no affected siblings of children with HABC have been reported, it is possible that this entity arises from a dominant de novo mutation, although autosomal-recessive inheritance remains possible. Disease severity ranges from severely affected infants presenting shortly after birth to more mildly affected children with initially normal development. In severe cases, children fail to achieve motor milestones and linguistic development, and show profound axial hypotonia. Some have nystagmus, and optic atrophy is possible. Spasticity is common. Extrapyramidal symptoms, comprising dystonia, rigidity, and choreoathetosis, are uniquely common to HABC relative to other white-matter disorders. Failure to thrive and microcephaly are common. In mildly affected children, unsupported walking is achieved within the first few years of life, sometimes on time, but is later lost. There is a combination of spasticity, extrapyramidal symptoms, and ataxia. cognitive impairment is mild, although patients tend to show cognitive decline in addition to deteriorating motor functions.

Recently published neuropathologic findings from one HABC patient detail slightly reduced white-matter volume, reduced oligodendrocytes, severe myelin deficiency, especially of deep white matter, and some white-matter loss, as indicated by the presence of macrophages in perivascular regions [van der Knaap et al., 2007]. Axons appeared relatively preserved. There was mild astrocytosis and a strong presence of microglia. The putamen was visible only as a small streak, and microscopy revealed substantial neuronal loss. Cerebral cortex was normal, both macroscopically and microscopically. In the atrophic cerebellum, there was loss of granule cells. Pyramidal tracts appeared degenerated in the brainstem and spinal cord. Metabolic investigations are normal in these children.

MRI shows hypomyelination. In some children, T2 white-matter signal is less hyperintense, indicating some myelin deposition. The cerebellum is atrophic, the vermis more so than the cerebellar hemispheres. Characteristic MRI features are atrophy or absence (in the later stages) of the putamen, apparent within the first year of life. The caudate is reduced, and in some patients, disappears entirely. Thalamic and pallidal volume remains normal. Over time, white-matter loss leads to supratentorial atrophy. The extent of basal ganglia and white-matter atrophy predicts clinical severity. These MRI features are considered diagnostic at this time.

Sialic Acid Storage Disorders

Salla disease (OMIM 604369) and infantile sialic acid storage disease (ISSD, OMIM 269920) are both caused by autosomal-recessive mutations in SLC17A5, coding for Sialin, a lysosomal membrane protein transporting sialic acid from lysosomes [Verheijen et al., 1999]. The gene is located on chromosome 6q14/15. Recently, it was shown that Sialin also functions as a shuttle for aspartate and glutamate in synaptic vesicles [Miyaji et al., 2008]. Free sialic acid accumulates in lysosomes of many cell types, including liver and kidney cells and cultured fibroblasts. In leukocytes, this accumulation causes vacuoles visible at light microscopic examination. Electron microscopy reveals membrane-bound vacuoles filled with fibrillogranular amorphous material. The pathogenesis of free sialic acid storage disease and the role of sialic acid remain unclear.

Both diseases are characterized by elevated excretion of free sialic acid in urine. Sialic acid is also elevated in other fluids, such as CSF. Recently, two siblings have been described who lack the characteristic sialuria; sialic acid was elevated only in CSF [Mochel et al., 2009]. Prevalent in Finland, Salla disease is characterized by seemingly normal early development, followed by presentation with hypotonia and ataxia in the second half of the first year of life. Nystagmus is also common. It may be evident in the neonatal period and frequently disappears. Many children also show strabismus. Spasticity develops slowly, and mild extrapyramidal symptoms are common in later stages. Mean age at walking is 4 years, with roughly one-third of patients who do not develop independent ambulation. Language is severely affected and usually dysarthric; patients are, at best, able to produce short sentences. Epilepsy with short, complex focal seizures is relatively common. In some patients, there is evidence of peripheral hypomyelination with decreased nerve conduction velocities. The disease is stable over a long period of time, with ultimate late progression. Additional symptoms may include short stature or hypogonadotropic hypogonadism. Facial features become coarse in adulthood. Otherwise, there is no evidence for dysostosis multiplex or hepatosplenomegaly, despite the presence of free sialic acid storage in liver and spleen. Life expectancy is normal [Aula et al., 2000].

ISSD is a much more severe disease, with neonatal presentation and rapid progression. Hydrops fetalis is possible. Neonates may show hepatosplenomegaly and ascites. They have fair hair and coarse features. Milestones of normal development are not acquired, and death occurs within the first couple of years.

A phenotype with intermediate severity relative to Salla disease and ISSD has also been identified.

MRI in patients with Salla disease shows hypomyelination [Sonninen et al., 1999] (Figure 71-3D). There is white-matter volume loss. Corpus callosum may be stringlike, especially in severe cases. There is usually cerebellar atrophy, and supratentorial atrophy is found in older patients. Thickening of the calvarium is another common radiologic feature. Proton MR spectroscopy reveals a high NAA peak, likely due to elevated free sialic acid, whose N-acetyl peak co-resonates with the N-acetyl peak of NAA [Varho et al., 1999].

Fucosidosis

Fucosidosis is another lysosomal storage disorder characterized by hypomyelination (OMIM 612280). Enzymatic defects in α-l-fucosidase result in fucose accumulation in tissues. Type I fucosidosis shows early onset and rapid progression, while type II develops with more insidious onset, presenting with nonspecific psychomotor retardation. Dysostosis multiplex and coarse features are mild in type II. Angiokeratomas are common and occur in 30 percent of patients under age 10. In type I, sweat contains a high concentration of sodium chloride. Bone marrow transplantation has been performed in individual cases. Its efficacy has not yet been empirically established, but it may slow the progression of the disease if performed early enough.

MRI shows hypomyelination. A characteristic feature of fucosidosis is high T1 and low T2 signal in globus pallidus, thalamus, and substantia nigra. Cerebral and cerebellar atrophy may be prominent in older patients [Prietsch et al., 2008].

Serine Synthesis Defects

Serine is synthesized by a three-step biochemical pathway, and defects in any of the three enzymes in this pathway have been shown to cause serine biosynthesis defects: 3-phosphoglycerate dehydrogenase (OMIM 601815), phosphoserine phosphatase (OMIM 172480), and phosphoserine aminotransferase (OMIM 610992). The biochemical hallmark of these disorders is low serine and glycine concentration in CSF. In plasma, serine concentration is often also decreased but may be normal, making CSF investigations an essential diagnostic tool for this group of disorders.

Children with 3-phosphoglycerate dehydrogenase deficiency are born microcephalic, and their development is grossly delayed. Epilepsy develops in the second half of the first year of life; West’s syndrome is one possible manifestation. Supplementation with serine and glycine is effective in seizure management. If treatment is commenced prenatally, head circumference at birth and development are normal [de Koning et al., 2004]. In untreated children, MRI shows hypomyelination and white-matter volume loss [de Koning et al., 2000]. Corpus callosum is thin and short. Myelination improves under treatment.

The first documented patient with phosphoserine aminotransferase deficiency presented in the neonatal period with severe epilepsy resistant to medical treatment and rapidly developing microcephaly. MRI showed supratentorial and brainstem atrophy. Supplementation with serine and glycine did not attenuate the seizures. The same treatment, if started before the development of symptoms, was shown to prevent epilepsy and enable normal development in the sibling of the proband [Hart et al., 2007].

Cockayne’s Syndrome and Trichothiodystrophy

Cockayne’s syndrome (CS) is a rare disease combining neurologic and non-neurologic features. This disorder and related disorders of DNA repair, such as cerebro-oculo-facial syndrome (COFS) and trichothiodystrophy (TTD), are genetically heterogeneous and are caused by mutations in CSA (CKN1 or DNA excision repair protein ERCC-8, responsible for 20 percent of CS cases), CSB (CKN2 or ERCC-6, responsible for most of the remainder of CS cases), XPB (ERCC3, OMIM 610651), XPD (ERCC2), XPG (ERCC5), ERCC1-XPF, TTDA and TTDN1 genes, and possibly others [Weidenheim et al., 2009].

The classic form, Cockayne’s syndrome type I, presents in the first year of life with failure to thrive; weight is more affected than length (“cachectic dwarfism”), and there is loss of subcutaneous fat, leading to a “wizened,” bird-like, progeroid face. Microcephaly also develops, usually by the end of the second year. Children develop contractures of the large joints, giving them a typical posture. Hands and feet are disproportionally large. Dental caries is prominent. Psychomotor development is also delayed, resulting in mild to severe cognitive impairment. Predominant neurologic features include ataxia and spasticity, which show slow progression. In late stages, peripheral neuropathy leads to muscle wasting and loss of the initially increased tendon reflexes. Over half of individuals develop sensorineural hearing loss. Most suffer from pigmentary retinal degeneration and cataracts. Autonomic dysfunction (hypolacrimia, hypohydrosis, miosis, acrocyanosis) is possible. In Cockayne’s syndrome type II, the clinical picture is much more severe, with growth failure already evident at birth. Loss or even absence of subcutaneous fat is striking. Joint contractures and kyphosis develop rapidly. Hypotonia is prominent initially, followed by development of spastic tetraparesis. Psychomotor development is absent or extremely delayed, with subsequent deterioration and early death. Subcutaneous fat loss has been treated in both types by early hypercaloric tube feeding, which allows reasonable growth in some children. Type III describes patients with milder forms of disease. Cutaneous photosensitivity is also characteristic of CS, occurring in 75 percent of all patients [Rapin et al., 2000].

In trichothiodystrophy (also called Tay’s syndrome), hair is dry, thin, and brittle. Polarization microscopy of affected hair reveals a typical tiger tail pattern. Structural hair abnormalities are due to a strong reduction in cysteine residues, which reduces disulfide cross-links in hair fibers. In some children, hair is lost after episodes with fever. Prominent cutaneous photosensitivity is also present and ichthyosis is possible. Nails are dystrophic. Neurologic symptoms are variable, and may include psychomotor delay, mild cognitive impairment, ataxia, pyramidal signs, frank spasticity, and nystagmus. As in CS, cataracts and retinal degeneration may also be seen.

Both syndromes are caused by defective nucleotide excision repair. Over 30 proteins are involved in this process. It eliminates DNA lesions induced by ultraviolet light. There are two major subpathways of nuclear excision repair: transcription-coupled repair, dealing with reparation of transcribed genes, and global genome repair, removing lesions in the entire genome. Defective DNA repair can be demonstrated by irradiating cultured skin fibroblasts with ultraviolet light and subsequently measuring unscheduled DNA synthesis. This unscheduled DNA synthesis is diminished in TTD and xeroderma pigmentosum patients. In CS, this unscheduled DNA synthesis is not significantly attenuated, but the otherwise rapid recovery of RNA and DNA synthesis after ultraviolet irradiation is adversely affected, indicating that the global genome repair is still functional. Additionally, reduction in basal transcription is also seen, an important signal for apoptosis. These defects of transcription, perhaps combined with activation of apoptosis, are thought to be mainly responsible for the neurologic symptoms in CS. Complementation assays in cultured cells could distinguish two different complementation groups, CS type I (OMIM 216400), caused by mutations in the gene coding for group 8 excision-repair cross-complementing protein (ERCC8), and type II (OMIM 133540), due to mutations in ERCC6. TTD is also heterogeneous, genetic defects having been identified in at least three different genes [Cleaver et al., 2009].

MRI of patients with CS shows hypomyelination, its degree corresponding to clinical severity. In severe cases with CS type II, hypoplasia of cerebellum and brainstem is possible. Basal ganglia calcifications are common. Similar features are seen in TTD, although calcifications are less common than in CS [Rapin et al., 2000; Adachi et al., 2006].

18q Minus Syndrome

In this disorder (OMIM 601808), the distal region of the long arm of chromosome 18 is deleted. It occurs de novo most commonly. The contiguous gene deletion usually involves the bands 18q22.3→qter. The gene for myelin basic protein (MBP), a component of healthy myelin, is located within this region. It has been postulated that haploinsufficiency for MBP leads to the myelin abnormalities observed in 18q minus syndrome. Heterogeneity in severity of clinical symptoms and hypomyelination between patients, despite consistent loss of MBP, is a focus of on-going inquiry. There is a well-investigated mouse model, the shiverer mouse, with homozygous rearrangements in the MBP gene [Nave, 1994], which lead to CNS, but no peripheral, hypomyelination. It is unknown why peripheral myelin is spared, despite MBP expression in peripheral nerves.

The disorder is stable, with a variety of dysmorphic features (microcephaly, hypertelorism, epicanthus, high or cleft palate, short neck, tapering fingers and clinodactyly, external ear anomalies, cardiac malformations, foot abnormalities) and neurologic abnormalities. Most patients show moderate to severe cognitive impairment, but cases with normal intelligence have been seen. Many suffer from sensorineural deafness. Patients may also show hypotonia in infancy, ataxia, nystagmus, and epilepsy. IgA deficiency and partial growth hormone deficiency are common.

MRI shows hypomyelination of variable, but usually mild, degree. The myelin signal in the cerebral hemispheres may be inhomogeneous, with patchy white matter abnormalities. Corpus callosum may be thin. There may be mild supratentorial atrophy [Linnankivi et al., 2006].

SOX10-Associated Disorders

These rare syndromes are caused by mutations in SOX10 on chromosome 22q13, which encodes a transcription factor for various genes, some involved in myelin formation and metabolism, such as GJB1 (connexin 32). These disorders are characterized by a white hair lock and hypomelanotic spots, sensorineural deafness, and Hirschsprung’s disease. Patients are affected with varying severity, ranging from antenatal onset with congenital arthrogryposis multiplex and severe neurologic abnormalities, to more mildly affected patients who lack neurologic manifestations (Waardenburg–Shah syndrome, WS4, OMIM 277580). The severe variant has been designated peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg’s syndrome, Hirschsprung’s disease, or PCWH (OMIM 609136). Consistent with a neurocristopathy, many features of this disease can be explained by defective differentiation or migration of neural crest cells. In the severe cases, MRI reveals hypomyelination [Touraine et al., 2000]. The milder phenotype of WS4 is explained by SOX10 haploinsufficiency, whereas the severe form, PCWH, is thought to be caused by a dominant negative mechanism. Mutations found in children with PCWH are all truncating and located in the last exon. These mutations, unlike SOX10 mutations leading to WS4, escape nonsense-mediated decay and can therefore exert their dominant negative effect on protein level [Inoue et al., 2004, 2007].

Neurologic symptoms of children with PCWH include delayed development, nystagmus, spasticity, and ataxia. In severe cases, neonates are already symptomatic, with profound hypotonia, seizures, or congenital arthrogryposis due to hypomyelinating neuropathy. Other possible symptoms are reduced tear and saliva production, anhidrosis, and severe failure to thrive, in addition to the classic syndromes of WS4. Neuropathologic investigations of a severely affected infant have shown absence of central and peripheral nervous system myelin at the age of 3 months [Inoue et al., 2002]. Detailed MRI features have not been reported for many patients, but preliminary cases suggest mild to severe hypomyelination, and possibly atrophic brainstem [Inoue et al., 1999].

Primary Demyelinating Leukodystrophies

These conditions comprise several of the “classic” leukodystrophies, and include Alexander’s disease, X-linked adrenoleukodystrophy, metachromatic leukodystrophy, and Krabbe’s disease.