Alexander’s Disease

Alexander’s disease (AxD, OMIM 203450)[Alexander, 1949] is associated with mutations in the gene encoding the glial fibrillary acidic protein (GFAP) [Brenner et al., 2001]. GFAP mutations are thought to confer gain-of-function mutations, and a mutation on a single allele is sufficient to cause disease. In most cases, mutations are sporadic, although familial cases are described in adult- or juvenile-onset cases. In familial cases, inheritance is autosomal-dominant. There is usually concordance in presentation within a family, such that a family with adult-onset presentation and subsequent infantile presentation has not been reported. There is no definite genotype–phenotype correlation, with the exception of the two most common mutations, R79 and R239. R239, in particular, is associated with earlier onset and poor prognosis.

AxD presents with two predominant clinical phenotypes. The infantile form typically presents before the second year of life. In very rare cases, patients present in the neonatal period with macrocephaly and delay in milestones, with both cognitive and motor deficits. Patients may present with seizures, often febrile, although these are rarely refractory to classic anticonvulsants. Pyramidal and sometimes extrapyramidal features develop, and children often lose motor skills in the first decade of life. Bulbar features, such as intractable vomiting, swallowing difficulties, and respiratory compromise, can be present early on or only develop over time. Hydrocephalus can become a significant clinical issue, and serial CT scans, in particular when abrupt clinical decompensation is noted, may help in clinical management. In some cases, surgical placement of a ventricular drainage system has provided clinical benefit. With aggressive supportive care, these children can enjoy periods of clinical stability, although the disease is relentless. Life span is variable.

The juvenile (2–12 years at onset) or adult (>12 years at onset) forms have historically been seen as distinct entities, but in reality are a continuum of very similar clinical features. These patients present with predominant motor dysfunction, often with progressive gait disturbance or fine motor difficulties, and clinically evident spasticity. Bulbar symptoms, in particular palatal myoclonus, can be very suggestive of the diagnosis. Over time, dysphonia and dysphagia can become increasingly debilitating. Dysautonomia is frequent. Sleep apnea is a commonly reported problem and sleep history should be monitored. In juvenile patients undergoing significant statural growth, scoliosis often evolves. In the older subjects, disease progression is slower than in the infantile cases, and many subjects continue to benefit from school and social activities for many years. In rare cases, juvenile and adult patients can present with atypical clinical manifestations, such as focal brainstem abnormalities that can be mistaken for brainstem gliomas.

Incidence and prevalence of AxD are not known. The infantile form was long assumed to be more common than the juvenile or adult variants, but an increasing number of adult cases are now being recognized, forcing clinicians to reconsider this characterization.

GFAP mutations are thought to result in decreased solubility of the glial fibrillary acidic protein, and accumulation of GFAP, along with vimentin, αβ-crystallin, and heat shock protein 27, result in Rosenthal fiber (RF) aggregation. RFs, accumulating in astrocytes, are thought to obstruct normal glial cell function and result in myelin destruction. RF accumulation in the ventricular collecting system is believed to cause the hydrocephalus seen in the clinical setting. Studies to improve pathophysiologic understanding of this disease and possible treatment strategies are on-going in an existing murine model of AxD. AxD is typically suspected from clinical presentation and characteristic MRI features. Typical AxD imaging features include frontal predominance of white-matter abnormalities, basal ganglia and or brainstem involvement, a periventricular rim of altered signal on T1- and T2-weighted imaging, and contrast enhancement of specific intracranial structures (see Figure 71-5A). The presence of four of five of these features makes diagnosis of AxD very likely and should prompt mutation testing [van der Knaap et al., 2001]. In very young infants and in the juvenile- or adult-onset cases, MRI may be less typical and involve only restricted brain regions. Additional features described in AxD imaging include predominant or isolated involvement of posterior fossa structures, multifocal tumor-like brainstem lesions, brainstem atrophy, and garland-like abnormalities along the ventricular wall [van der Knaap et al., 2005, 2006]. MR spectroscopy can be helpful in the diagnosis if it shows a lactate peak in affected tissues, but may also lead to inappropriate evaluations for mitochondrial cytopathies. There have been reports of findings of elevations of GFAP protein in CSF [Kyllerman et al., 2005], but this test is not used as a clinical tool.

X-Linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy (XALD, OMIM 300100) is associated with mutations in the ABCD1 gene [Mosser et al., 1993] encoding a peroxisomal membrane transporter. This disorder follows X-linked inheritance, and often, when male children are diagnosed with the childhood-onset cerebral form, disease manifestations are recognized in obligate female carriers or male relatives of the proband. Differences in disease manifestations are known to occur with identical genotype, and even within a sibship, underscoring the likely effect of other genetic factors on clinical presentation. Genotype does not predict very long chain fatty acid levels or specific clinical prognosis. Genetic changes reported include missense mutations, nonsense mutations, frameshift mutations, small deletions/insertions, and large deletions.

XALD is characterized by three predominant phenotypes. The best known is the childhood-onset cerebral form (35 percent of affected individuals), in which male children of school age (usually 4–8 years) present with a prior history of behavioral or cognitive changes. These are often initially misdiagnosed as attention-deficit disorder or hyperactivity. The progressive nature of the symptoms, overlaid with progressive motor difficulties, deteriorating school function and handwriting, altered perception of speech, and worsening behavior problems, usually brings the child to medical attention, and neuroimaging frequently is highly suggestive of the diagnosis. Disease course is variable, but complete symptom development occurs over a range of 6 months to 2 years. Over time, significant motor involvement develops, with a spastic quadriplegia. In addition, bulbar dysfunction becomes problematic, and often necessitates gastrostomy tube feeding. Adrenal insufficiency is a life-threatening complication of XALD, and studies suggest that a large number of subjects with the childhood-onset cerebral form have adrenal insufficiency at time of diagnosis. Adrenal function should be tested at diagnosis and monitored thereafter to permit symptomatic management.

A second frequent type of presentation is adrenomyeloneuropathy (AMN; 40–45 percent of affected individuals), characterized by onset in young adult males (20s to middle age) of progressive gait abnormalities, sexual dysfunction, and abnormalities of sphincter control. In some cases, predominant spinal cord symptoms are associated with significant abnormalities on MRI of the brain, and in a subset of these, relentless neurologic deterioration will occur. In the remainder of the subjects, the disease appears slowly progressive. Adrenal insufficiency should be sought at diagnosis and at follow-up, although it is less frequent than in the cerebral childhood-onset form.

A third type is isolated adrenal insufficiency. On occasion, patients with adrenoleukodystrophy may first present with an Addisonian crisis, and no neurologic features or abnormalities on neuroimaging. XALD should be considered in the differential diagnosis of isolated adrenal insufficiency in a male subject. Finally, approximately 20 percent of female carriers may have symptoms of progressive gait disturbance and spastic paraparesis similar to what is seen in subjects with AMN. Onset is usually in middle age.

Of note, an allelic disorder, with a neonatal presentation of cholestasis, hypotonia, and developmental delay, is caused by a contiguous gene deletion syndrome involving the 5′ end of ABCD1. This disorder is called contiguous ABCD1 DXS1357E deletion syndrome (CADDS), and is clinically distinct from XALD [Corzo et al., 2002].

The estimated prevalence of XALD is estimated to be 1:20,000–1:50,000. The estimated prevalence of hemizygotes (affected males) and heterozygotes (carrier females) is estimated at 1:16,800 [Bezman et al., 2001].

The pathophysiology of XALD is believed to arise from accumulation of saturated very long chain fatty acids (SVLCFA) within the brain. This accumulation is thought to result from defective peroxisomal fatty acid oxidation of SVLCFA, caused by defective transport by the mutated ABCD1, possibly due to altered adenosine triphosphate (ATP) binding [Gartner et al., 2002; Roerig et al., 2001].

Diagnosis is based on characteristic clinical presentation and suggestive MRI features. MRI shows a predominance of occipital findings (see Figure 71-5D), although frontal and corpus callosum variants are recognized. The affected white matter appears hyperintense on T2 and hypointense on T1. Characteristically, there is a rim of enhancement around the abnormal tissue that can be very helpful in establishing the diagnosis, as few other leukodystrophies, with the exception of Alexander’s disease, show significant contrast enhancement. When XALD is suspected, appropriate clinical tests include fasting VLCFA testing on plasma, which shows an excess in SVLCFA with specific abnormalities in C26:0, C24:0/C22:0, and C26:0/C22:0 ratios [Moser et al., 1981]. Mutation testing of the ABCD1 gene provides molecular confirmation of the diagnosis, with attention to the 7 percent of cases with deletions or rearrangements.

Treatment with Lorenzo’s oil or diets rich in oleic and erucic acids, in addition to VLCFA restriction, can alter VLCFA levels. As treatment strategies for XALD evolve, interest in newborn screening is growing. This can be done using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to test for the analyte 1-hexacosanoyl-2-lyso-sn-3-glycero-phosphorylcholine (26:0-lyso-PC)[Hubbard et al., 2009; Raymond et al., 2007]. As with many disorders now being considered for widespread newborn screening, the clinical benefit of early diagnosis remains to be established.

Treatment of XALD depends on the stage and type of disease manifestations, and is still research-based. Treatment with Lorenzo’s oil, which decreases hexacosanoic acid (C26:0), does not appear to stop or reverse cerebral disease once it has begun, although there are reports of improved long-term stability in presymptomatic patients in open-label studies with no placebo control [Moser et al., 2007]. The use of Lorenzo’s oil is investigational and should be performed in the context of a clinical research protocol. Bone marrow transplantation (BMT) is indicated in children with early-stage, cerebral-form XALD, as evidenced by active disease on MRI. Family members of an affected proband should be tested by VLCFA and monitored for early MRI evidence of cerebral involvement to identify candidates for BMT. These patients should be evaluated by clinicians with specific expertise in this disorder. Gene therapy is a potential future tool and research studies are under way. Supportive care can improve comfort and quality of life for XALD patients. Careful monitoring and treatment of adrenal insufficiency should be part of therapeutic management.

Metachromatic Leukodystrophy

Metachromatic leukodystrophy (MLD, OMIM 250100) [Greenfield, 1933; Von Hirsch and Peiffer, 1955; Suzuki and Chen, 1966] is caused by mutations in the ARSA gene encoding arylsulfatase A [Stein et al., 1989; Austin et al., 1964] on chromosome 22q13.31, and is inherited in an autosomal-recessive manner. Homozygous or compound heterozygous ARSA mutations impair arylsulfatase A degradation of sulfatides, causing sulfatide accumulation within the brain and peripheral nervous system. Complete loss of arylsulfatase A activity (“I” or “O” alleles) is typically associated with early infantile MLD. Partial loss of arylsulfatase A activity (“R” or “A” alleles) is typically associated with juvenile- or adult-onset MLD. Compound heterozygosity with an I and A allele usually results in juvenile-onset MLD. Rarely, subjects with microdeletions of 22q13 and deletion of the ARSA gene with an MLD-causing mutation on the other allele have been diagnosed with MLD.

Additionally, there are common polymorphisms of ARSA (referred to as “PD” alleles), which result in sufficient residual activity to avoid sulfatide accumulation. These cause arylsulfatase pseudodeficiency, rather than MLD. These polymorphisms, either homozygous or compound heterozygous with MLD-causing ARSA mutations, do not cause MLD. Enzymatic evidence of low arylsulfatase activity must be accompanied by accumulation of sulfatides linked to pathogenic ARSA mutations before establishing a diagnosis of MLD.

MLD is characterized by three clinical subtypes, defined primarily by age at presentation. Late infantile MLD patients usually present by age 2, following a period of apparently normal development. Initial clinical manifestations include gait disturbance, ataxia, dysarthria, or cranial nerve features such as esotropia. Initially, symptoms may be slowly progressive or may plateau, sometimes followed by a rapid loss of motor skills over a few weeks, during which time the diagnosis is commonly made. Tonic spasms with pyramidal and extrapyramidal dysfunction, and loss of peripheral reflexes are striking. Eventually, disease progresses to severe motor impairment with loss of volitional movements, bulbar dysfunction, loss of vision and hearing, and seizures. The time course of deterioration is highly variable, and, with maximal supportive care, death often occurs much later than reported in older texts. The disease, however, is relentlessly progressive after the initial period.

Juvenile MLD patients present between age 4 and puberty (12–14 years). Patients presenting after this age are classified as having adult-onset MLD. Patients often present with cognitive and behavior difficulties. Younger juvenile-onset patients often show early motor involvement and may also show rapid decline. Clumsiness, gait problems, dysarthria, incontinence, and worsening behavioral problems occur later in the course, and often prompt etiologic evaluation and diagnosis. Patients may have seizures, most often complex partial seizures. Progression is similar in juvenile MLD to that described in infantile MLD, with a slower course.

Adult-onset MLD patients may present with motor symptoms common to earlier presentations. Alternatively, patients may develop severe neuropsychiatric symptoms, often leading to misdiagnosis until motor features evolve. Patients may initially present with predominant peripheral neuropathy or with seizures. Arylsulfatase A deficiency results in impaired breakdown of sulfatides (cerebroside sulfate or 3-0-sulfo-galactosylceramide). Sulfatides comprise approximately 5 percent of myelin within the central and peripheral nervous system. They are also found at high concentrations in the kidneys and testes. Sulfatide accumulation in glial cells is thought to lead eventually to myelin destruction, glial cell death, and the resultant neurologic phenotype. The only other organs known to show manifestations are the kidneys (with excretion of large amounts of sulfatides in urine but no clinical symptoms), the gallbladder, and the testes. Microscopic pathology is characterized by myelin loss, paucity of oligodendroglia, reactive astrogliosis, and metachromatically staining material in the white matter.

MLD diagnosis is often suspected based on clinical manifestations of motor impairment with a peripheral neuropathy. Typical MRI features include sparing of arcuate fibers and a rim of subcortical white matter, with involvement of periventricular and deep white matter in the supratentorial CNS (see Figure 71-5B). Involved white matter takes on the appearance of radiating stripes that can be highly suggestive of the disorder and reflects accumulation of sulfatides in perivascular macrophages. These radiating stripes are also present in other disorders, however, including Krabbe’s disease. In early stages or in adult cases, incomplete neurologic findings can complicate diagnosis, and early involvement of the corpus callosum may provide a clue. Occasionally, isolated involvement of cranial or peripheral nerves has been seen in the early stages of disease.

When the diagnosis is suspected, enzymatic assessment of peripheral leukocytes for arylsulfatase A activity is often performed. If abnormal, confirmatory evidence of disease, such as excess urinary sulfatides, should be sought to avoid the diagnostic pitfall of pseudodeficiency. To offer appropriate genetic counseling and carrier testing for family members, molecular confirmation should be sought by sequencing the ARSA gene. In view of evolving treatment studies, some states are now providing newborn screening that includes lysosomal disorders such as MLD. This practice is highly debated due to lack of evidence of complete penetrance and perfect genotype–phenotype correlation, and uncertainty regarding management of affected patients.

MLD is the focus of intensive research exploring approaches to restore partial enzymatic activity. BMT may be indicated in patients with MLD, but its success is dependent on the age and stage of disease progression. Candidates for BMT should be evaluated by persons with particular expertise in this disorder. Enzyme replacement therapy is not yet available but may be a future tool in the management of these subjects. The advent of possible treatments has reinforced the need for early and appropriate diagnosis, especially in siblings of index patients. Additionally, symptomatic treatment can greatly impact quality of life. In addition to usual management of spasticity, attention to possible extrapyramidal symptoms and to painful neuropathy should guide therapy. Possible seizures should be evaluated and treated as appropriate.

Metachromatic Leukodystrophy-Like Variants

In some cases, there is strong clinical suspicion of MLD, including presence of urinary sulfatides, but ARSA sequencing is normal. Two disorders should be considered in this clinical situation. In cases with excess urinary sulfatides and clinical picture consistent with MLD, but normal arylsulfatase A activity, deficiency of arylsulfatase activator protein (saposin B) (OMIM 249400) should be tested. Diagnostic confirmation requires studies of sulfatide metabolism in fibroblast cultures or sequencing of the prosaposin gene. Another variant with overlap with MLD is multiple sulfatase deficiency (MSD) (OMIM 272200), in which a defect of the formylglycine-generating enzyme (FGE) causes a deficiency in the function of multiple sulfatases, including arylsulfatase A and also arylsulfatase B, arylsulfatase C, iduronate sulfatase, and heparan-N-sulfamidase in leukocytes. In these subjects, excess sulfatides in the urine are accompanied by abnormal mucopolysaccharides. Subjects have clinical manifestations of MLD in addition to mucopolysaccharidoses. MRI findings in both of these disorders are similar to MLD.

Krabbe’s Disease or Globoid Cell Leukodystrophy

Krabbe’s disease (OMIM 245200) is caused by autosomal-recessive mutations in the gene encoding galactosylceramidase (GALC) on chromosome 14q31 [Austin et al., 1970; Suzuki and Suzuki, 1971; Wenger et al., 1974; Zlotogora et al., 1990; Chen et al., 1993]. Two recurring mutations are associated with specific phenotypes. One common 30-kb deletion results in the classic infantile form in the homozygous state or when compound heterozygous with another mutation associated with severe disease. The 809G>A mutation is associated with the late-onset form of Krabbe’s disease, even when connected to mutations associated with severe disease. There is limited genotype–phenotype correlation for other mutations, however, and different disease courses have been seen in the same family.

Krabbe’s disease has two main forms. In the classic infantile form, onset is within the first 6 months, typically following a few months of apparently normal development. Patients present with irritability, hypertonia, and peripheral nerve involvement (stage I). CSF protein is elevated. Symptoms will often lead to neuroimaging, and MRI suggests the diagnosis. This stage is followed by rapid deterioration, leading to decerebrate posturing and almost opisthotonic positioning of the head and neck (stage II). Optic atrophy develops and pupillary light reflexes are abnormal. Seizures often occur at this stage. This period is often followed by a longer period of slow deterioration in infants in a near-vegetative state (stage III). Infants often succumb to respiratory infections in the first years of life, although supportive care has been known to extend life. Late infantile-onset forms (after 6 months of age) present with symptoms of vision loss, developmental regression, and spasticity. Juvenile- (after 4 years of age) and adult-onset cases present with variable symptoms, including gait dysfunction, loss of vision, seizures, or cognitive-behavioral changes. The rapidity of decline appears to correlate with age at onset, with younger patients (late infantile and juvenile) progressing more rapidly than adult-onset cases.

Prevalence has been reported to be about 1 in 100,000 births in the US and Europe.

In Krabbe’s disease, deficiency of GALC results in psychosine accumulation, which is thought to lead to apoptosis of glial cells. On pathology specimens, microscopic evaluation demonstrates accumulation of globoid cells, multinucleated giant cells, in affected central white matter and deep gray nuclei. Peripheral nerve demyelination may also be demonstrated.

Diagnosis is suspected based on combined motor and peripheral nerve involvement. Neuroimaging can also guide diagnosis, with CT demonstrating highly suggestive hyperdensity of the thalami, caudate, corona radiata, and, in some cases, cerebellum and brainstem. MRI is less pathognomonic than in other disorders; however, early involvement of the brainstem and cerebellar white matter, in particular the hilus of the dentate nucleus, can be helpful in establishing the diagnosis (see Figure 71-5G). Thickening of the optic nerves and chiasm has been reported. Over time, the most significant involvement occurs in deep and periventricular white matter, with relative sparing of U fibers early on. The corpus callosum is affected. Radiating stripes can be seen within the affected white matter. There is often prominent atrophy of the brain. Late-onset forms may present with similar MRI patterns, or less typical ones, such as changes limited to the corticospinal tracts in adult-onset cases. In some instances, enhancement of the gray–white matter junction, cranial nerves, or spinal nerve roots can be seen.

When Krabbe’s disease is suspected, GALC enzyme activity (using radiolabeled natural substrate galactosylceramide [gal-cer]) can be measured in vitro in leukocytes and cultured skin fibroblasts. Individuals with Krabbe’s disease have very low GALC enzyme activity (0–5 percent of normal activity). Carrier screening using GALC activity is unreliable. Newborn screening using GALC enzyme activity has been established and is in use in some states. Abnormal GALC enzyme activity can be followed up by molecular testing using targeted analysis for the most common mutations, followed by sequencing and deletion studies.

Disease-modifying treatments have focused on the use of hematopoietic stem cell transplantation, but the risks of this procedure are great, and treatment must be initiated before onset of significant clinical symptoms; in the infantile form it may be of limited utility. Decisions regarding pursuit of this type of therapy for Krabbe’s disease should be made in a center with a large clinical experience in this disorder. Newborn screening may allow earlier detection, but age of onset and disease severity are unpredictable for the late-onset cases, stirring debate as to its merits. Research into other treatment modalities, including gene therapy, enzyme replacement therapy, neural stem cell transplantation, substrate reduction therapy, and chemical chaperone therapy, are being explored in animal models but are not yet established for use in clinical trials.

Saposin A Deficiency

An infant with abnormal myelination resembling Krabbe’s disease was found to have a mutation in the saposin A region of the prosaposin (PSAP) gene (OMIM 611722) [Spiegel et al., 2005]. Prosaposin is one of several known sphingolipid activator proteins, and interacts with the enzyme GALC to catalyze the hydrolysis of lipids.

Canavan’s Disease

Canavan’s disease (CD; OMIM 271900), previously known as spongy degeneration of the CNS of the Van Bogaert–Bertrand type, is caused by a deficiency of aspartoacylase, encoded by ASPA [Kaul et al., 1993; Matalon et al., 1988]. This disorder has been documented since at least the 1950s [De Vries et al., 1958], but a biochemical marker was not identified until nearly 30 years later. Inheritance is autosomal-recessive. Incidence is increased in patients of Ashkenazi Jewish descent, with two common mutations, p.Glu285Ala and p.Tyr231X, responsible for 98 percent of disease alleles, facilitating carrier screening in this population. In addition, p.Ala305Glu is responsible for 40–60 percent of the disease-causing alleles in non-Jewish populations, and for 1 percent of disease-causing alleles in the Ashkenazi Jewish population [Kaul et al., 1994]. A final splice-site mutation, c.433-2A>G, is responsible for 1 percent of disease-causing alleles in the Ashkenazi Jewish population. Beyond these, there are many pathogenic mutations with no clear genotype–phenotype correlation, and affected siblings may have a variable course, despite identical genotypes. Although less common, deletions and duplications can be disease-causing alleles.

Most patients with CD present with the infantile form. These children appear normal until approximately 3–6 months of life, when hypotonia with loss of head control, irritability, loss of milestones, and head circumference growth becomes notable. Over time, spasticity replaces hypotonia, and optic atrophy, extrapyramidal movement disorders, seizures, and autonomic disturbances develop. In time, a more chronic vegetative state develops, which can evolve over years. Tonic extensor spasms are often described. More rarely, a congenital variant is seen in which poor feeding, irritability, and hypotonia become evident within days after birth, followed by rapid deterioration and death. Some patients with prolonged development of early milestones have been characterized as having juvenile onset, but the course generally overlaps the infantile form and it is unclear whether this is truly a distinct variant [Traeger and Rapin, 1998].

CD is caused by aspartoacylase deficiency, resulting in accumulation of NAA in the brain and its excretion in the urine. The synthesis and role of NAA and the related compound, NAAG, within the brain remain poorly understood and are the subject of active research. NAA accumulation is thought to be the cause of myelin vacuolization and astrogliosis, although the mechanism is unclear. Hypotheses include altered neurotransmission, osmotic disturbances, and abnormal synthesis of myelin lipids. Histopathologic studies have documented myelin loss and innumerable small vacuoles, predominantly in the deep cortex and subcortical regions, giving the brain the spongiform appearance that resulted in its early name, “spongy degeneration.” Myelin loss is accompanied by astrogliosis, and in the cortex, swollen astroglial cells.

Biochemical testing is diagnostic in CD, with NAA elevations detectable in urine, plasma, and CSF, and decreased aspartoacylase activity in cultured fibroblasts. Targeted mutation analysis is often used as a first-line diagnostic strategy. Panels testing the four most common disease-causing alleles will diagnose almost 100 percent of affected Ashkenazi Jewish patients, and 40–60 percent of affected non-Jewish patients (www.genereviews.org). Full sequencing and detection of deletions or duplications are used to identify the remainder of subjects with CD. Diagnosis may also be suggested by MRI features, such as confluent involvement of subcortical white matter, extending in severe cases to the central and periventricular white matter in a centripetal fashion, and signal abnormalities of the globus pallidus and thalamus, with sparing of the caudate and putamen. Signal abnormalities of the brainstem and cerebellar white matter can be seen. Over time, extensive white-matter atrophy leads to ventriculomegaly.

No disease-specific treatment is available for CD at this time, although supportive care is very important. Several therapeutic trials are on-going, including the use of lithium citrate, glyceryl triacetate, and gene therapy.

eIF2B-Related Disorder (Vanishing White Matter Disease)

eIF2B-related disorder and its various allelic clinical subtypes (vanishing white matter disease OMIM 603896 [van der Knaap et al., 1997] or CACH [Schiffmann et al., 1994], ovarioleukodystrophy [Fogli et al., 2003; Schiffmann et al., 1997], and Cree leukoencephalopathy [Fogli et al., 2002]) are caused by mutations in one of the five genes (EIF2B1–5) encoding a complex, eIF2B [Leegwater et al., 1999, 2001; van der Knaap et al., 2002]. eIF2B, or eukaryotic translation initiation protein 2B, is the guanine nucleotide exchange factor for eIF2, another critical protein in translation initiation. eIF2B-related disorders are inherited in an autosomal-recessive manner, with 65 percent of mutations found on the gene EIF2B5 [van der Knaap et al., 2002; Maletkovic et al., 2008]. Mutations across the five genes are numerous, and in most cases are private mutations, with a compound heterozygous presentation, although some patients are homozygous for the more common mutations. No phenotype is known to exist for heterozygous carriers. There is known genotype–phenotype correlation for certain more common genotypes, including homozygous R113H mutation-positive subjects [van der Knaap et al., 2004], who have an adult onset with milder phenotype, and the homozygous R195H mutation-positive subjects, who have a more severe early-onset presentation [Fogli et al., 2002].

Patients with eIF2B mutations may present with a variety of clinical syndromes. The best-known presentation is the infantile or early childhood presentation with “vanishing white matter disease.” These children, previously healthy, present with acute neurologic decompensation after events of physiologic stress, including fever, falls, or fright. The precipitating event is usually followed after several hours by acute motor dysfunction, typically hypotonia or ataxia, and sometimes even coma. The child may die during the acute event, or survive with neurologic sequelae, and be vulnerable to future events of decompensation. On occasion, no acute event is noted, but loss of skills is gradual and relentlessly progressive. Over several years, progressive motor dysfunction results in spastic quadriparesis, cranial nerve involvement, including ophthalmoparesis and optic nerve atrophy, and severe bulbar dysfunction.

At opposite ends of the phenotypic spectrum, eIF2B mutations can also present in a connatal form, where neurologic disability is evident from birth, with additional findings such as ovarian dysgenesis, cataract, or hepatomegaly, or may present in an adult form with progressive spastic paraparesis. Allelic disorders include Cree leukoencephalopathy, whose name derives from the Cree Indian population in Alaska; the R195H founder mutation results in aggressive early infantile presentation, with rapid progression and early death [Fogli et al., 2002]. Another allelic disorder is ovarioleukodystrophy, in which adult women present with primary ovarian failure and minimal, if any, neurologic features.

Incidence and prevalence of eIF2B-related disorders are not known. eIF2B-related disorder is thought to be caused by alterations in the cellular response to endoplasmic reticulum stress and alterations in protein translation [Kantor et al., 2008; van Kollenburg et al., 2006a,b; Kantor et al., 2005; Schiffmann and Elroy-Stein, 2006]. eIF2B plays a crucial role in the initiation of protein translation, acting as the guanine nucleotide exchange factor for eIF2alpha, another translation initiation factor. When a cell undergoes physiologic stress, protein translation is altered and misfolded proteins often accumulate within the endoplasmic reticulum. Cell-salvaging pathways include eIF2B as a critical modulatory element. It is unknown, however, how alterations in a ubiquitously expressed housekeeping gene result in a primarily glial cell phenotype.

Diagnosis of eIF2B-related disorder is based on appropriate clinical history, neuroimaging, and molecular genetics. Common MRI features include diffuse signal abnormality of the supratentorial white matter, with less constant signal abnormalities in the cerebellar white matter, brainstem, thalamus, and globus pallidus. In supratentorial white matter, T2 FLAIR shows low signal intensity, isointense with CSF, and suggestive of white-matter rarefaction and cystic degeneration. On sagittal T1-weighted images, a pattern of radiating tissue strands may be seen, compatible on pathology with preserved tissue (see Figure 71-5C). MRI findings of eIF2B-related disorder are nearly pathognomonic, except in cases with very early or late onset. In appropriate clinical conditions, molecular studies of the EIF2B genes is appropriate, usually beginning with EIF2B5, which harbors 65 percent of identified pathogenic mutations. If molecular testing does not clarify the diagnosis, biomarkers such as CSF glycine [van der Knaap et al., 1999] and decreased CSF asialotransferrin [Vanderver et al., 2008] can help further investigate the likelihood of eIF2B-related disorder.

There is currently no disease-modifying therapy for eIF2B-related disorder. Avoidance of head trauma and infectious triggers is suggested, but no data on the success of these strategies exist. Supportive therapy, including careful attention to orthopedic and pulmonary complications in patients with severe spastic quadriparesis, is the only management option currently available for eIF2B-related disorder.

Aicardi–Goutières Syndrome

Aicardi–Goutières syndrome (AGS; OMIM 225750 [AGS1], 610181 [AGS2], 610329 [AGS3], and 610333 [AGS4]) is a genetically heterogeneous disorder associated with mutations in a series of genes encoding nucleases or putative nucleases. These include TREX1 [Crow et al., 2006], SAMHD1 [Rice et al., 2009], and RNAseH2 A, B, and C [Crow et al., 2006]. In most cases, AGS appears to be autosomal-recessive, although rare cases of heterozygotes with AGS phenotypes are reported [Rice et al., 2007]. Additionally, rare patients with clinical diagnoses of systemic lupus erythematosus have been found to harbor heterozygous mutations in TREX1 [Lee-Kirsch et al., 2007]. In addition, a disorder now referred to as autosomal-dominant retinal vasculopathy with cerebral leukodystrophy (RVCL) is allelic with AGS. This disorder has previously been described as cerebroretinal vasculopathy/hereditary retinal vasculopathy/hereditary endotheliopathy with retinopathy, nephropathy, and stroke (CRV/HRV/HERNS) [Grand et al., 1988; Gutmann et al., 1989; Jen et al., 1997], associated with linkage to 3p21 [Ophoff et al., 2001] and with heterozygous mutations in TREX1 [Richards et al., 2007]. RVCL is a rare disorder with retinal vasculopathy, migraine, Raynaud’s phenomenon, stroke, and dementia with onset in middle age. Allelic disorders with AGS with an autosomal-recessive inheritance include familial chilblain lupus [Rice et al., 2007], Cree leukoencephalitis, and toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus (TORCH)-like disorders. Approximately 83 percent of patients with characteristic AGS-related clinical findings have mutations in TREX1, RNAseH2A, RNAseH2B, or RNAseH2C [Rice et al., 2007]. In those individuals with identified molecular changes, 65 percent had disease caused by TREX1 or RNAseH2B mutations. Moreover, almost all individuals with RNAseH2B mutations had at least one mutation in exons 2, 6, or 7. These observations may allow for a targeted initial screening strategy when performing diagnostic molecular testing.

AGS is characterized by leukoencephalopathy, basal-ganglia or white-matter calcifications, and elevated CSF interferon-alpha [Rice et al., 2007; Lebon et al., 1988; Bonnemann and Meinecke, 1992; Tolmie et al., 1995; Goutieres et al., 1998; Kuijpers, 2002], with no detectable infectious etiology. Patients present most often in the neonatal period or in infancy. Early-onset patients may present in the neonatal period with a syndrome that mimics in utero viral infections, including Coombs-positive hemolytic anemia and autoimmune thrombocytopenia, elevated transaminases, microcephaly, seizures, vasculitic skin lesions, and cerebral calcifications. Often, these patients are initially suspected of having a congenital CMV, rubella, or HIV infection [Crow and Livingston, 2008]. A genetic cause may be suspected only after the birth of a second affected child. This condition may also present in older infants with progressive microcephaly, dystonia, seizures, and developmental delay, as well as sterile pyrexias, lupus-like skin and joint manifestations [Aicardi and Goutieres, 2000], progressive intracranial calcifications, chronically elevated CSF lymphocytes [Giroud et al., 1986], autoantibodies[Ramantani et al., 2010], and elevated CSF pterins.

AGS has been described as a neurodegenerative disorder, but does not truly fit that characterization, as children may remain clinically stable for long periods of time. This disorder may more aptly be characterized as a heritable disorder of cell intrinsic immunity. Developmental regression, associated with painful skin lesions and systemic manifestations, often in an episodic manner, occurs in the early years of life, followed in many cases by years of stability. Progressive cerebral atrophy and cerebral calcifications are seen. Many children succumb later in life to medical complications, but children living into their teens and later are known.

AGS, caused by a series of genes encoding known or putative nucleases, is thought to be caused by the accumulation of intrinsic nucleic acids. Although this is presumed to trigger innate cellular immunity and an interferon-alpha-mediated immune response, the mechanisms through which this occurs remain poorly understood. In addition, the specific result of this immune dysfunction, and how this results in the myelin loss and calcifying microangiopathy described in this disorder, remain uncertain.

Suggested minimal criteria for diagnosis are intracranial calcifications with abnormal CNS white matter and no infectious explanation, characteristic clinical findings, such as chilblains, and/or CSF findings of leukocytes, pterins [Wassmer et al., 2009], or interferon-alpha. Molecular confirmation of mutations in TREX1 [Crow et al., 2006], SAMHD1 [Rice et al., 2009], RNAseH2 A, B and C [Crow et al., 2006] is helpful, and may obviate the need for CSF testing in the future. However, it is important to consider the genetic heterogeneity of this disorder, and the fact that many AGS patients do not have mutations in these genes. Neuroimaging characteristics can be very helpful in the diagnosis of AGS. The pattern of calcifications is usually that of punctate calcifications seen in the periventricular white matter and the basal ganglia, most often the globus pallidus and the putamen. In some cases, larger calcifications can be seen. Calcifications may also be present in the brainstem or the cerebellum. In some cases, in particular early in the course, calcifications may be absent altogether. MRI images show high T2 signal and low T1 signal abnormalities in the white matter, most prominently in the frontal and temporal lobes, and atrophy may be significant.

Effective treatments for AGS have yet to be discovered. Severe irritability, chilblains, and systemic secondary complications remain extremely challenging to manage.

Cerebroretinal Microangiopathy with Calcifications and Cysts

Cerebroretinal microangiopathy with calcifications and cysts (CRMCC, OMIM 612199) [Briggs et al., 2008] is thought to be on a continuum with leukoencephalopathy with calcifications and cysts (LCC) [Labrune et al., 1996; Nagae-Poetscher et al., 2004] and Coats’ plus syndrome [Crow et al., 2004; Tolmie et al., 1988]. An underlying genetic etiology has not been identified, although reports of affected siblings, male and female probands, and children born to consanguineous families suggest an autosomal-recessive inheritance pattern.

CRMCC, LCC, and Coats’ plus syndrome reflect a spectrum of affected patients with presumed microvascular disorders affecting the brain, eyes, liver, intestines, and bones. Presentation ranges from early infancy to adulthood. Pre- and postnatal growth retardation is common. The patient may develop visual symptoms leading to an ophthalmologic examination before or after the onset of neurologic symptoms. Ophthalmologic evaluation identifies bilateral retinal telangiectasias and retinal exudates. Patients may develop spontaneous fractures of the long bones or skull and have documented osteopenia. Life-threatening intestinal bleeding may occur, and many patients are found to have cirrhosis or portal hypertension. Less often, patients may have dystrophic nails, hyperpigmented skin lesions, and sparse hair with premature graying. Because of progressive neurologic symptoms varying by age and ranging from hypotonia and focal motor deficits to ataxia and extrapyramidal symptoms, neuroimaging is often performed and suggests the diagnosis. Patients may succumb to complications of their neurologic status, such as aspiration pneumonia, although the clinical course is variable and slow disease progression is described. It is also important to note that not all organ systems are involved in every patient.

A number of pathologic reports appear to suggest that CRMCC is an obliterative microangiopathy [Briggs et al., 2008]. This may explain the neurologic, ocular, intestinal, and hepatic findings, although it does not explain other pathogenic features.

Diagnosis is informed by the constellation of clinical symptoms described above, and findings on diagnostic evaluations. Neuroimaging demonstrates large progressive calcifications of cerebral white matter, basal ganglia, thalamus, cerebellar white matter, and dentate. The pattern of calcifications is distinct from those seen in other disorders described in this section, and should be considered in the context of other features for diagnosis of CRMCC. Additionally, leukoencephalopathy and parenchymal cysts are notable and often progressive findings. Standard symptom-directed clinical evaluations may identify evidence of bone-marrow abnormalities, fractures, osteopenia, cirrhosis, and gastrointestinal bleeding. No laboratory-based biomarker or diagnostic molecular test is currently available for this disorder.

There is currently no disease-specific treatment for CRMCC. Supportive care for the multi-organ involvement seen in this disorder is crucial, with early management of potential complications. Rehabilitative services for the complex needs of this patient population, including visual, motor, and speech and language disabilities, is likely to be beneficial.

Bandlike Intracranial Calcification with Simplified Gyration and Polymicrogyria

Bandlike intracranial calcification with simplified gyration and polymicrogyria is a recently described phenotypic group [Briggs et al., 2008; Abdel-Salam and Zaki, 2009]. Two series of patients have been characterized by severe postnatal microcephaly, dysmorphic facial features, developmental arrest, and seizures. Neuroimaging demonstrates simplified sulcation, and a large calcified band most often in the frontal white matter and basal ganglia, as well as brainstem calcifications. Inheritance pattern is autosomal-recessive, although a specific molecular etiology has yet to be identified. Reports of other patients with cerebral dysgenesis, intracranial calcification, and no evidence of TORCH infection exist in the literature [Reardon et al., 1994; Burn et al., 1986; Kalyanasundaram et al., 2003], but none exhibits all the symptoms described in these subjects. It remains to be seen whether this initial description represents a more widely distributed phenotype.

Cockayne’s Syndrome

Cockayne’s syndrome, as discussed above, is a disorder characterized by cachectic dwarfism, neurologic disability, cutaneous photosensitivity, pigmentary retinopathy, leukodystrophy, and occasionally, intracranial calcifications. Disorders allelic with Cockayne’s syndrome, including COFS and TTD, are less likely to have significant intracranial calcifications, although these have been described in a restricted number of cases [Linna et al., 1982].

Spondyloenchondrodysplasia

Spondyloenchondrodysplasia (SPENCD, OMIM 271550) is a disorder with generalized enchondromatosis and platyspondyly that may also develop progressive intracranial calcifications. Its molecular cause is not known and its inheritance pattern is unclear. The bone abnormalities in these subjects should suggest this diagnosis when cerebral calcifications are present.

Cytomegalovirus

Although a number of pre- and perinatal infections can result in significant brain disorders, CMV deserves a special mention in this chapter because of its significant white-matter injury, leading to frequent concerns about an underlying inherited leukoencephalopathy. In addition, CMV frequently, but not always, results in intracranial calcification. This disorder is discussed in the section below on cystic leukoencephalopathies. Other infections can cause significant white-matter changes and intracranial calcification, including HIV, tuberculosis, and toxoplasmosis, but clinical features should indicate that these are unlikely to be consistent with an inherited leukoencephalopathy.

Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL, OMIM 125310) is a primarily cerebral microangiopathy, presenting in adults with a history of migraine headaches, progressive early-onset cerebrovascular disease, and early-onset dementia; leukoencephalopathy and subcortical infarcts are revealed on neuroimaging. Over 90 percent of individuals have mutations in NOTCH3, the only gene known to be associated with CADASIL. CADASIL is inherited in an autosomal-dominant manner. De novo mutations appear rare, so family history may support the diagnosis. The pathologic diagnosis of CADASIL is based on the finding of electron-dense granules in the media of arterioles that can often be identified by electron microscopic (EM) evaluation of skin biopsies. MRI findings can also guide diagnosis, including early white-matter T2 hyperintensities in the temporal lobe and extreme capsule. Another common radiologic feature is subcortical lacunar lesions, typically linearly grouped at the gray–white matter junction. Microbleeds can result in calcifications in addition to the above-mentioned leukoencephalopathy. Several other hereditary disorders affecting cerebral vasculature, including cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) [Yanagawa et al., 2002], recently associated with mutations in the HtrA serine protease 1 (HTRA1) gene [Hara et al., 2009], and hereditary systemic angiopathy (HSA) [Winkler et al., 2008], can all be associated with leukoencephalopathy and intracranial calcifications.

Intracranial Calcification

Intracranial calcification associated with leukoencephalopathy is also seen in mitochondrial disease, and is sporadically reported for various disorders, including mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) [Pronicki et al., 2002].

Dihydropterine Reductase Deficiency

Dihydropterine reductase deficiency can be associated with leukoencephalopathy and calcifications [Miladi et al., 1998; Coskun et al., 1990]. This disorder is further discussed below.

Cerebrotendinous Xanthomatosis

Cerebrotendinous xanthomatosis is associated with leukoencephalopathy and calcifications. This disorder is further discussed below.

Bilateral Occipital Calcifications

Bilateral occipital calcifications with leukoencephalopathy, seizures, and clinical or subclinical celiac disease have also been reported as a distinct entity [Iglesias et al., 2000; Lea et al., 1995; Crosato and Senter, 1992].

Familial Hemophagocytic Lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHLH) is characterized by proliferation and infiltration of hyperactivated macrophages and T lymphocytes. It can be caused by mutations in a number of genes, including PRF1 (FHL2, OMIM 603553) [Stepp et al., 1999], UNC13D (FHL3, OMIM 608898) [Feldmann et al., 2003], STX11 (FHL4, OMIM 603552) [zur Stadt et al., 2005], and Munc 18-2 (FHL5, OMIM 613101) [zur Stadt et al., 2009], although a number of patients have no identified mutation. Inheritance is autosomal-recessive.

FHLH is characterized by acute illness with prolonged fever (lasting more than 7 days), and features associated with macrophage activating syndrome, including hepatosplenomegaly, cytopenias (anemia, thrombocytopenia, and neutropenia), hypertriglyceridemia and/or hypofibrinogenemia, and bone marrow hemophagocytosis. Neurologic symptoms are highly variable and may include motor deficits and seizures. Onset is usually within the first few months of life, but sometimes in the neonatal period or in older childhood. MRI may show hypomyelination or demyelination. MRI may also show multifocal abnormalities at the gray–white matter junction, hemorrhage, atrophy, focal necrosis, and edema. Calcifications can be seen in areas of abnormal brain tissue [Takano and Becker, 1995]. Allogeneic hematopoietic stem cell transplantation is the only curative therapy and should be undertaken as early as possible for children with confirmed FHLH.

Megalencephalic Leukoencephalopathy with Subcortical Cysts

Megalencephalic leukoencephalopathy with subcortical cysts (MLC, OMIM 604004) [van der Knaap et al., 1995] is an autosomal-recessive disease associated with mutations in the gene encoding MLC1 protein [Leegwater et al., 2001; Topcu et al., 2000], thus named because at least 15 percent of MLC subjects have no mutation at MLC1 and locus heterogeneity is anticipated. Synonyms include leukoencephalopathy with swelling and discrepantly mild course, cysts, infantile leukoencephalopathy and megalencephaly, van der Knaap’s disease, and vacuolating leukoencephalopathy. There is a founder effect in the Agarwal community in India, with a common genotype (p.Cys46LeufsX34), as well as some more common mutations in individual populations, including persons of Libyan Jewish descent, Turkish Jewish descent, and Japanese descent [Leegwater et al., 2001; Topcu et al., 2000; Ben-Zeev et al., 2002; Saijo et al., 2003; Singhal et al., 2003; Tsujino et al., 2003; Gorospe et al., 2004; Leegwater et al., 2002].

Postnatal macrocephaly is the predominant presenting symptom, noted in the first year, although macrocephaly may be present at birth. No molecularly confirmed cases of MLC without megalencephaly have been identified. This is of diagnostic importance, since a number of other disorders can present with temporal lobe subcortical cysts, including AGS, CMV infection, and RNAse T2-deficient leukoencephalopathy, among others [Henneke et al., 2005]. Stabilization of head growth rate often occurs after age 1, up to 4–6 standard deviations above normal. Patients may have normal early development, or mild delays in motor and cognitive milestones. Later in life, patients develop a spastic ataxia of variable severity. Epilepsy, often easily controlled, is common. Cognitive deterioration is usually late and mild. Dysarthric speech can be particularly debilitating in MLC.

Pathophysiology in MLC1-related MLC is thought to involve altered cellular trafficking in mutated MLC1, a cellular membrane protein expressed in astrocytes. It is localized with the dystrophin glycoprotein complex in astrocytic endfeet in perivascular, subpial, and subependymal regions [Boor et al., 2007]. MLC1 mutations are believed to reduce membrane expression of this protein [Duarri et al., 2008]. Downstream effects on transport across the blood– and CSF–brain barriers have been hypothesized [Boor et al., 2005], but have yet to be empirically established.

Diagnosis in MLC is based on clinical manifestations and typical MRI features. These include a swollen appearance of subcortical white matter; diffuse white-matter signal abnormality with relative preservation of central structures such as the corpus callosum, internal capsule, brainstem, and cerebellum; and development of subcortical cystic structures, most prominently in the anterior temporal and frontoparietal regions (see Figure 71-5F). Over time, severe white-matter structural atrophy can ensue. In typical cases, genetic testing for splice-site mutations and deletions, in addition to missense or nonsense mutations, can identify alterations in many cases, although in at least 15 percent of typical MLC presentations, no mutations in MLC1 can be found.

No disease-specific treatment for MLC currently exists, although supportive service for speech and gait difficulties, and medical management of seizures are important to quality-of-life maintenance.

RNAse T2-Deficient Leukoencephalopathy

A subset of subjects with subcortical cysts and leukoencephalopathy without megalencephaly [Henneke et al., 2005] appear to have mutations in RNase T2, encoded by RNAseT2 [Henneke et al., 2009]. This is a recently described disorder and shares clinical and neuroradiological features with congenital CMV infection. In RNAse T2-deficient leukoencephalopathy there is no evidence of CMV infection, and familial cases suggest autosomal-recessive inheritance. Affected subjects have normo- or microcephaly, developmental delay, and epilepsy, in some cases. MRI reveals striking abnormalities, with multifocal white-matter abnormalities, and temporal lobe cystic structures similar to those seen in CMV. CT reveals scattered calcifications in some patients. The pathophysiologic mechanism eliciting a clinical and radiologic phenotype so reminiscent of congenital CMV remains unknown, and no known treatment for this disorder currently exists.

Congenital Cytomegalovirus Infection

Infants with congenital CMV infection may present acutely in the neonatal period with evidence of encephalopathy, neonatal hepatitis, thrombocytopenia, and anemia, or may present chronically with progressive microcephaly, developmental delay, and sensorineural hearing loss. These subjects may pose diagnostic challenges when MRI reveals cerebral white-matter abnormalities.

Diagnosis of congenital CMV infection may be made in cases of known maternal infection, and confirmed by neonatal viremia established by CMV PCR in urine or blood. In these cases, identified white-matter abnormalities, with or without gyrational abnormalities involving the brain and cerebellum, should not necessarily raise concern for an additional underlying disorder, but are associated with the identified congenital infection. In many cases, however, infants become symptomatic after the neonatal period, when a definitive PCR diagnosis of infection can no longer easily be established. These patients are often characterized as having unsolved leukoencephalopathies. MRI criteria suggestive of the diagnosis of congenital CMV include multifocal cerebral white-matter lesions located in the deep white matter, predominantly in the parietal region, associated with dilated temporal horns and subcortical cysts in the temporal lobe [van der Knaap et al., 2004]. In cases in which abnormal gyration is suspected, such as polymicrogyria, white-matter abnormalities may be diffuse or multifocal. These MRI criteria are not specific, however, and cannot establish a definitive diagnosis. If saved, newborn blood spots can permit retrospective CMV PCR [van der Knaap et al., 2004; O’Rourke et al., 2008; Lopez-Pison et al., 2005].

Cerebroretinal Microangiopathy with Calcifications and Cysts

As discussed above, CRMCC [Briggs et al., 2008] can present with a significant progressive cystic leukoencephalomalacia, although the cerebral calcifications and multisystem involvement differentiate it from other cystic leukoencephalomalacias.

Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL, OMIM 611105) [van der Knaap et al., 2003] is caused by autosomal-recessive mutations in DARS2, encoding mitochondrial aspartyl-tRNA synthetase [Scheper et al., 2007]. Patients are compound heterozygous for pathogenic mutations [Scheper et al., 2007].

LBSL is characterized by slowly progressive cerebellar and sensory ataxia, spasticity, and dorsal column dysfunction. Onset ranges from late childhood to adulthood. In some patients, gait is never normal, but most patients have initial normal milestones. The predominant presenting feature is spastic ataxia, accompanied by distal abnormalities in vibration and proprioceptive sensation. Loss of motor function is slowly progressive and may result in loss of independent ambulation. Rarely, seizures are seen. There may be mild cognitive difficulties. A few patients have a paroxysmal and partially reversible neurologic decline associated with physiologic stressors, including febrile infection or minor head trauma [Marjo and van der Knaap, 2005].

Mitochondrial dysfunction results in a wide range of myelin abnormalities, suspected to arise from disturbance in energy production and use by glial cells. DARS2 encodes mitochondrial aspartyl-tRNA synthetase, which incorporates aspartic acid into mitochondrial DNA-encoded proteins. LBSL could be classified as a “mitochondrial” leukoencephalopathy, but although mutant proteins were found to have decreased ability to aminoacylate tRNA^ASP in experimental conditions, no abnormalities in mitochondrial complex activity have been identified [Scheper et al., 2007]. This finding leaves the role of DARS2 mutations in the clinical and radiologic abnormalities found in LBSL unresolved.

Before linkage studies identified DARS2 as the etiologic locus [Scheper et al., 2007], diagnosis of LBSL was based exclusively on MRI pattern recognition, as no biomarker exists for this disorder. Classic MRI features include patchy cortical and cerebellar white-matter abnormalities, with striking tract involvement over the entire length of the CNS, including the spinal cord (see Figure 71-6A). Initial reports note involvement of the pyramidal tracts from the internal capsule to the spinal cord corticospinal tracts; the sensory tracts, including the dorsal column, medial lemniscus, thalamus, and corona radiata; cerebellar peduncles; and the trigeminal nerve and mesenchymal trigeminal tracts [van der Knaap et al., 2003; Serkov et al., 2004; Linnankivi et al., 2004]. The corpus callosum is involved, usually more posteriorly than anteriorly. Elevated lactate in affected white matter on MR spectroscopy is often seen, but not always, DARS2 sequencing of this gene has become the diagnostic standard.

Alexander’s Disease

As described above, AxD patients may have significant and sometimes isolated brainstem signal abnormalities, particularly in late-onset cases, in which clinical and radiologic features are primarily related to brainstem structures [van der Knaap et al., 2005, 2006]. Of note, posterior fossa abnormalities are sometimes misdiagnosed as gliomas, and only correctly identified by histopathologic evidence of excessive Rosenthal fiber aggregation.

Polyglucosan Body Disease and Adult Polyglucosan Body Disease

Polyglucosan body disease (PGBD, OMIM 263570) [Robitaille et al., 1980] is an adult-onset leukoencephalopathy with upper and lower neuron motor impairment, distal sensory neuropathy, and neurogenic bladder, characterized by polyglucosan body accumulation in nervous structures. GBE1, encoding 1,4-alpha-glucan-branching enzyme [Lossos et al., 1991], is the only gene known to be associated with adult polyglucosan body disease (APBD) [Lossos et al., 1998]. Inherited in an autosomal-recessive manner, this disorder is allelic with glycogen storage disorder type IV, although these usually much younger patients often have little to no residual enzyme activity. Further, a distinct clinical picture dominated by hepatic, cardiac, and muscle symptoms, with rare clinically important neurologic features, is seen [McMaster et al., 1979; Schroder et al., 1993]. Rare patients with PGBD have been reported with a childhood onset of neurologic disability [Felice et al., 1997]. Increased prevalence of APBD is thought to exist in the Ashkenazi Jewish population, with a common homozygous GBE1 mutation, p.Tyr329Ser, although other ethnic groups are known to be involved as well. Of importance in genetic counseling, manifesting carriers have been noted, including those with the common p.Tyr329Ser mutation [Ubogu et al., 2005; Massa et al., 2008].

Patients with PGBD present in the fifth to seventh decades. Significant upper motor neuron impairment with prominent pyramidal tract signs is seen, along with cerebellar ataxia and extrapyramidal movement disorders or Parkinson’s-like presentations. Combined with these features, striking lower motor neuron impairment is seen, with atrophy and fasciculations, and this disorder may be mistaken for amyotrophic lateral sclerosis. Patients may have distal sensory loss, and hyporeflexia, further complicating neurologic evaluation. Electrophysiologic testing demonstrates axonal sensorimotor radiculopolyneuropathy with slowed conduction nerve velocity and denervation. A neurogenic bladder may be seen, and in some cases these symptoms are the presenting complaint. Cognitive difficulties evolve with time, but tend to be mild and slowly progressive.

The hallmark of APBD is accumulation of polyglucosan bodies in the brain and nerves. Polyglucosan bodies (PBs) are diastase-negative glucose polymers that stain with periodic acid–Schiff (PAS) on histological samples. When examined ultrastructurally, PBs are characterized by granular and filamentous material within the axonal structure and may be associated with loss of myelination. PB accumulation is believed secondary to glycogen branching enzyme deficiency. Within central and peripheral nervous structures, PB accumulation with resultant axonal demyelination [Massa et al., 2008] is thought to result in the clinical phenotype. Importantly, PBs are not specific to APBD, and their presence should be interpreted in the context of the clinical picture.

Diagnosis is usually suggested by the clinical features and the pattern of white-matter abnormalities on MRI. Patients with APBD have confluent but poorly demarcated periventricular white-matter abnormalities, with early sparing of the U fibers and corpus callosum. Cerebellar and brainstem signal abnormalities, most extensive around the fourth ventricle and the long tracts of the brainstem, are also seen. Most pathognomonic of APBD are sagittal FLAIR signal abnormalities outlining the pons (see Figure 71-6B). In the early stages, MRI abnormalities are sufficiently nonspecific that misdiagnosis of multiple sclerosis is common. Definitive diagnosis requires additional supportive evidence. GBE1 sequencing is abnormal in over 90 percent of patients with clinically suggested APBD (www.genereviews.org). It is unknown whether the remainder of subjects have mutations in another unidentified gene, or whether other occult genetic changes result in an altered glycogen branching enzyme. Sural nerve biopsy or skin biopsy can demonstrate evidence of excess PBs. Deficiency of glycogen branching enzyme can also be demonstrated in cultured skin fibroblasts if GBE1 sequencing is equivocal.

There is currently no effective treatment for PGBD, although a randomized controlled trial of triheptanoin is on-going. Supportive care for the urologic disturbances and gait dysfunction can considerably increase patient safety and quality of life.

Autosomal-Dominant Leukodystrophy with Autonomic Disease (Lamin B1)

Autosomal-dominant leukodystrophy with autonomic disease (ADLD, OMIM 169500) [Marklund et al., 2006; Melberg et al., 2006; Eldridge et al., 1984; Schwankhaus et al., 1994; Coffeen et al., 2000; Leombruni et al., 1998; Quattrocolo et al., 1997] is an adult-onset leukoencephalopathy caused by duplications in LMNB1 on 5q23, encoding lamin B1 [Padiath et al., 2006; Meijer et al., 2008]. Apparent de novo cases are reported in addition to cases of autosomal inheritance. Recently, linkage to the 5q23 region was established in a family with ADLD-like features, but without identifiable LMNB1 alterations. These patients did, however, show increased expression of lamin B1 in lymphoblastoid cells, suggesting a degree of locus heterogeneity [Brussino et al., 2009].

The first neurologic sign is often autonomic dysfunction, such as urgency in urination, impotence, constipation, anhidrosis, and postural hypotension. Disease onset is typically in the fourth to sixth decades. These symptoms are followed by pyramidal tract dysfunction and ataxia, with slow progression, sometimes over decades. No peripheral neuropathy is reported. Mild cognitive decline may be seen.

Lamin B1 is overexpressed in ADLD. This protein is an intermediate filament expressed in the nuclear lamina within the nuclear envelope. Believed to be involved in either altered nuclear envelope stability or transcriptional regulating, lamin B1 duplications have a yet unknown mechanism that disrupts myelin homeostasis. Available histopathologic reports suggest loss of myelin in the cerebrum and cerebellum, preserved oligodendrocytes, and mild astrogliosis. No evidence of inflammation is seen.

Before the genetic locus was known, clinical history and MRI features were the mainstay of diagnosis. Notable radiologic features include confluent white-matter changes in supratentorial regions, predominantly affecting the deep white matter, with relative sparing of the periventricular white matter and the subcortical fibers. In some cases, predominance in the rolandic regions and pyramidal tracts is seen at onset, evolving over time into diffuse white-matter abnormalities. The corpus callosum is relatively spared, but can show posterior abnormalities. The posterior limb of the internal capsule is often involved. Abnormal signal is seen in brainstem tracts, and the upper and middle cerebellar peduncles are often involved (see Figure 71-6C) [Bergui et al., 1997; Schwankhaus et al., 1988]. Testing for LMNB1 duplications can provide important diagnostic and genetic counseling information.

No disease-specific treatment currently exists, although supportive care for urinary dysfunction, postural hypotension, and gait disturbance can provide significantly improved quality of life for affected subjects.

Neuroaxonal Leukodystrophy with Spheroids

Neuroaxonal leukodystrophy with spheroids is an important leukoencephalopathy with primarily adult presentation. Neuroaxonal leukodystrophy with spheroids, also known as hereditary diffuse leukoencephalopathy with spheroids (HDLS, OMIM 221820) [Axelsson et al., 1984], has no known genetic cause. It is possibly the same entity as pigmentary orthochromatic leukodystrophy (POLD) [Marotti et al., 2004], with overlap in clinical symptoms, histopathology, and neuroimaging [Wider et al., 2009]. Until a biomarker or genetic etiology is identified, however, it will be difficult to clarify the spectrum of this disorder. Inheritance appears to be autosomal-dominant, although autosomal-recessive inheritance has been reported in POLD, and reports of sporadic mutations exist for both disorders.

The clinical manifestations of HDLS are fairly protean, and it is likely underdiagnosed. Onset occurs most commonly in the fifth decade, although a broader range of age of presentation has been reported, including in adolescence [Wider et al., 2009]. Behavioral and cognitive changes tend to predominate in the early stages, and are most often initially classified as depression and anxiety [Wider et al., 2009]. These neuropsychiatric symptoms may be severely debilitating, and often result in diagnosis of frontal dementia. Gait impairment, with pyramidal and extrapyramidal features, is often seen, sometimes with ataxia. Epilepsy is not uncommon. Peripheral nerve involvement is not reported. Profound dementia leads to death, usually within a decade of onset.

Pathophysiology remains poorly understood in this disorder. Pathologic specimens show myelin loss and axonal destruction, alongside axonal spheroids and lipid-laden, autofluorescent sudanophilic macrophages. The primary pathophysiologic event in HDLS is unknown, although mechanisms such as oxidative damage [Ali et al., 2007] and post-translational modification of myelin-associated proteins [Giordana et al., 2005] have been hypothesized.

Diagnosis is usually suspected based on familial inheritance, clinical features, and neuroimaging. Neuroimaging is nonspecific, and may show predominance of frontoparietal lobe involvement, with periventricular, corpus callosum, and central white matter. White-matter abnormalities may be nonconfluent and patchy, particularly in early-onset cases. White-matter abnormalities extend through the internal capsule, involving the pyramidal tracts in the brainstem [van der Knaap et al., 2000; Freeman et al., 2009]. Severe frontal atrophy and ventricular enlargement often develops (see Figure 71-6G). Definitive diagnosis can only be established by autopsy or brain biopsy. Identification of axonal spheroids and autofluorescent sudanophilic macrophages on pathologic specimens is particularly helpful for establishing this diagnosis. There is no specific treatment for HDLS at this time.

Defects in Glucose/Carbohydrate Metabolism

Disorders Involving Amino Acid Metabolism

See also Chapter 32.

Purines and Pyrimidines

Disorders Involving Urine Organic Acid Excretion

Vitamin/Co-Factor Deficiencies

Disorders of Metal Metabolism

Fatty Acid Metabolism

Lysosomal Disorders

While metachromatic leukodystrophy and Krabbe’s disease could each be considered in this section, they have long been classified as leukodystrophies due to their specificity for central and peripheral white matter, and they are discussed elsewhere. Salla disease and infantile sialic acid storage disease are discussed in the section on hypomyelinating leukodystrophies. This section focuses on lysosomal disorders not classically defined as leukodystrophies, but in which significant white-matter abnormalities are common.

Peroxisomal Disorders

Adrenoleukodystrophy, one of the best-understood leukodystrophies, is a peroxisomal disorder, although its predominant white-matter abnormalities have long classified it as a leukodystrophy and so it is not discussed here. Disorders of peroxisome biogenesis and single peroxisomal protein deficiencies will be reviewed.

Mitochondrial Leukoencephalopathies

A broad range of mitochondrial disorders (see also Chapter 37) can present with significant white-matter abnormalities. Beyond the representative disorders discussed here, white-matter involvement can also be seen in MELAS, Leber’s hereditary optic neuropathy, Kearns–Sayre syndrome, Leigh’s syndrome, and a growing list of other nuclear mutations causing mitochondrial disease.