Tools for Diagnosis of Leukodystrophies and Other Disorders Presenting with
White Matter DiseaseAdeline Vanderver, MD
AddressDepartment of Neurology, Childrens National Medical Center, 111 Michigan Avenue, NW, Washington, DC 20010, USA. E-mail : firstname.lastname@example.org
Current Neurology and Neuroscience Reports 2005, 5:110118Current Science Inc. ISSN 1528-4042Copyright 2005 by Current Science Inc.
Advances in biochemical techniques, molecular genet-ics, and neuroimaging, particularly magnetic resonance imaging, have made possible the diagnosis of a signicant proportion of leukodystrophies. A specic diagnosis allows the physician to give prognostic information, monitor for known complications, and ultimately may allow disease specic therapeutics. The purpose of this review is to familiarize the reader with pertinent tools in the diagnosis of leukodystrophies and other white matter disorders that may present with white matter disease. The rst section discusses conditions that may mimic leukodystrophy and how to exclude them. Although not meant to be an exhaustive summary, several key disor-ders and their clinical, biochemical, and neuroimaging features are presented. The second section focuses on classically described leukodystrophies and their diagnosis. Finally, a third section provides a diagnostic algorithm to help the clinician in the diagnosis of the patient with leukodystrophy.
IntroductionHeritable disorders affecting the white matter can have dysmyelination as a predominant manifestation (leukodystrophy) or as part of a systemic disorder (leuko-encephalopathy). Individually, white matter diseases are rare, but as a group they have a prevalence of one in 5000 to 6000 live births. Several groups of metabolic disorders, notably, mitochondrial cytopathies, peroxi-somal disorders, amino acid disorders, urea cycle defects, organic acidemias, and lysosomal disorders, can result in classically described leukodystrophies or have associated leukoencephalopathy. A signicant proportion of patients with white matter disease have yet unidentied disorders.
The combination of clinical, biochemical, neuro-imaging, and molecular genetic evaluations will allow the clinician to reach a diagnosis when the patient has a known white matter disease. Many of these same tech-niques are being used to classify novel leukodystrophies, and familiarity with them will allow the clinician to diagnose new disorders as they are identied.
Inborn Errors of Metabolism and Other Disorders with Associated LeukoencephalopathyThe term leukodystrophy is typically reserved for diseases with prominent disorders of central (and peripheral) myelin. Many disorders with systemic manifestations may have associated white matter abnormalities and these are usually referred to as leukoencephalopathies. Most often, the white matter ndings are incidental in view of the devastating nature of these disorders. However, on occasion, in the disorders described here, white matter disease has been a prominent clinical or radiologic nding, with a paucity of other features to suggest the diagnosis. Therefore, these disorders enter the differential diagnosis in the evaluation of the patient with a white matter disease (Table 1). The summary in the following text is not meant to be exhaustive, merely indicative of the variety of disorders that can have associated white matter abnormalities.
Endocrinopathies or vitamin decienciesTreatable disorders, such as endocrinopathies or vitamin deciencies, should always be considered. White matter changes can be seen in autoimmune thyroid disease, and thyroid function studies should be tested in any undiag-nosed leukoencephalopathy. Vitamin B
while most often presenting with recognizable clinical features, has been reported to present with prominent central nervous system ndings and should be excluded. Although animal models suggest that vitamin E and nutritional folate deciency could present with white matter changes, the author found no reports supporting this diagnosis clinically. Biotinidase deciency results
Diagnosis of Leukodystrophies and Other White Matter Disease Vanderver 111
in a clinical picture that includes seizures, hypotonia, ataxia, breathing problems, hearing loss, optic atrophy, skin rash, and alopecia. Patients have a diffuse leuko-encephalopathy, which is reversible after treatment with biotin, although neurologic sequelae remain.
A systemic disorder, Langerhans cell histiocytosis, can result in white matter parenchymal changes resem-bling a leukodystrophy . However, these are associated with other recognizable manifestations, including lesions of the craniofacial bone and skull base, with or without soft tissue extension, and intracranial extra-axial changes that should help identify the disorder. If suspicion arises, careful review of neuroimaging features and skull lms may be helpful.
Disorders of carbohydrate metabolismDisorders of carbohydrate metabolism may present with white matter ndings. Galactosemia may present with diffuse hypomyelination. There are isolated reports of individual patients with congenital disorders of glyco-sylation having diffuse white matter hypodensities, stroke-like white matter changes, or small, focal white matter abnormalities. If systemic ndings or structural brain abnormalities support the diagnosis, it is not unrea-sonable to pursue this diagnosis.
Amino acidopathiesAmino acidopathies may present with prominent leukoencephalopathy. Phenylketonuria is now usually diagnosed by newborn screening, and the classic symp-toms are rarely seen. Magnetic resonance imaging (MRI) studies in patients with phenylketonuria reveal symmetric, patchy, or band-like areas of white matter abnormality involving the posterior/periventricular white matter. Lesions may extend to the frontal and sub-cortical white matter, and include the corpus callosum. Dihydropteridine reductase deciency is a rare cause of hyperphenylalaninemia, which is characterized by severe and progressive neurologic impairment, despite early and accurate dietary control of plasma phenylalanine. Imaging studies may show prominent white matter abnormalities .
Urea cycle disorders represent one of the most common groups of inborn errors of metabolism and may result in leukoencephalopathy. The most common of these, ornithine transcarbamylase deciency, is an X-linked disorder that typically presents with neonatal hyper-ammonemic episodes that result in leukoencephalopathy due to brain injury from hyperammonemia . In male patients with partial deciencies and certain heterozygous female patients, presentation is less dramatic and of later onset . In this situation, MRI may manifest focal white matter abnormalities and the diagnosis of a leuko-dystrophy may be considered (Table 2).
Maple syrup urine disease is caused by impaired metabolism of the branched-chain amino acids leucine,
isoleucine, and valine. In classic cases, infants present in the rst week of life with poor feeding, vomiting, opisthotonus, seizures, and respiratory distress. In these cases, neuroimaging reveals white matter changes due to reversible edema . The cerebellar white matter is markedly involved. In milder cases of maple syrup urine disease, the clinical picture may comprise mild to moder-ate mental retardation with a clinical history of periods of coma, acidosis, lethargy, and hypoglycemia. In these cases, a picture of delayed myelination or dysmyelination may be seen [9,10].
There are isolated reports of other amino acid disorders with associated white matter disease. Hyperprolinemia has been associated with a diffuse leukoencephalo-pathy. Nonketotic hyperglycinemia, in which signicant plasma and cerebrospinal uid (CSF) glycine elevations are seen, has been associated with supratentorial white matter abnormalities . White matter abnormalities are also seen in gyrate atrophy of the choroid and retina, a disorder with hyperornithinemia.
Organic acid disordersGlutaric aciduria type 1 is caused by a deciency of the enzyme glutaryl coenzyme A (CoA) dehydrogenase. It is characterized by symptom onset in infancy with macrocephaly, hypotonia, choreoathetosis, dystonia, and encephalopathic crises associated with an intercurrent illness or surgery. Rare adult-onset cases are described. Imaging ndings include characteristic structural changes such as widening of the operculae, acute subdural hemorrhage, and signal changes of the basal ganglia, dentate nucleus, substancia nigra, and the pontine medial lemniscus . White matter changes have been reported in the periventricular white matter .
Sjogren Larsson syndrome is an inborn error of lipid metabolism caused by a defect in fatty aldehyde dehydro-genase. Characteristic clinical ndings include ichthyosis, mental retardation, spastic diplegia or tetraplegia, speech delay, short stature, and retinal abnormalities. On neuroimaging, white matter abnormalities are present in periventricular regions, the centrum semiovale, the corpus callosum, and frontal and parietal lobes . There is sparing of subcortical U bers.
Branched-chain organic acidurias such as propi-onic acidemia and methylmalonic acidemia have also rarely been associated with diffuse supratentorial white matter dysmyelination.
Mitochondrial cytopathiesMitochondrial disorders are caused by mutations of nuclear or mitochondrial DNAencoded genes involved in oxidative phosphorylation. Mutations in these critical genes are associated with multisystem disorders that may manifest with neurologic, cardiac, endocrine, gastrointestinal, hepatic, renal, and/or hematologic involvement and may present with highly