Leukodystrophies by Raphael Schiffmann MD (Dr
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Leukodystrophies By Raphael Schiffmann MD (Dr. Schiffmann, Director of the Institute of Metabolic Disease at Baylor Research Institute, received research grants from Amicus Therapeutics, Protalix Biotherapeutics, and Shire.) Originally released January 17, 2013; last updated November 25, 2016; expires November 25, 2019 Introduction Overview Leukodystrophies are a heterogeneous group of genetic disorders affecting the white matter of the central nervous system and sometimes with peripheral nervous system involvement. There are over 30 different leukodystrophies, with an overall population incidence of 1 in 7663 live births. They are now most commonly grouped based on the initial pattern of central nervous system white matter abnormalities on neuroimaging. All leukodystrophies have MRI hyperintense white matter on T2-weighted images, whereas T1 signal may be variable. Mildly hypo-, iso-, or hyperintense T1 signal relative to the cortex suggests a hypomyelinating pattern. A significantly hypointense T1 signal is more often associated with demyelination or other pathologies. Recognition of the abnormal MRI pattern in leukodystrophies greatly facilitates its diagnosis. Early diagnosis is important for genetic counseling and appropriate therapy where available. Key points • Leukodystrophies are classically defined as progressive genetic disorders that predominantly affect the white matter of the brain. • The pattern of abnormalities on brain MRI, and sometimes brain CT, is the most useful diagnostic tool. • Radial diffusivity on brain diffusion weighted imaging correlates with motor handicap. • X-linked adrenoleukodystrophy is the most common leukodystrophy and has effective therapy if applied early in the disease course. • Lentiviral hemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy shows promise. Historical note and terminology The first leukodystrophies were identified early last century. Both Nissl and Alzheimer coincidentally reported metachromatic staining of the white matter of an adult patient with what we would now call metachromatic leukodystrophy (Alzheimer 1910; Nissl 1910). Globoid cell leukodystrophy, or Krabbe disease, was described in 1916. Hallervorden suggested that these globoid cells may contain kerasin or cerebroside. Biochemical and histochemical studies confirmed the presence of cerebroside in globoid cells (Austin 1959), and galactocerebroside was the only glycolipid that could produce globoid cells when injected into the central nervous system of experimental animals. Jatzkewitz and Austin independently identified the metachromatic substance as sulfatide, a sulfated glycolipid (Jatzkewitz 1958; Austin 1959). Subsequently, Austin and colleagues and Mehl and Jatzkewitz showed that the sulfatide accumulation was caused by reduced activity of arylsulfatase A, the lysosomal enzyme that hydrolyzes galactose-- -sulfate from sulfatides (Austin et al 1964; Mehl and Jatzkewitz 1965). Until the early 1990s, the known leukodystrophies were metachromatic leukodystrophy, Krabbe disease, Canavan disease, Alexander disease, adrenoleukodystrophy, Pelizaeus-Merzbacher disease, and 2 forms of adult-onset autosomal dominant leukodystrophies (Aicardi 1993). As of 1994, a series of new leukodystrophy syndromes have been described (Schiffmann et al 1994; Kevelam et al 2016). Typically, the etiology of the leukodystrophy syndromes is discovered a few years after their initial clinical description. One difficulty has been in deciding which clinical syndrome qualifies as a leukodystrophy and which is just a leukoencephalopathy or a disorder associated with white matter abnormalities on imaging or on pathological examination. The term leukoencephalopathy has been applied to both heritable and acquired disorders, such as toxic, acquired vascular, or infectious. There were a number of attempts to identify a list of leukodystrophies, and the most recent was done by consensus of physician experts in the field (Table 1) (Vanderver et al 2014). Leukodystrophies do not include disorders characterized as heritable leukoencephalopathies (Table 2) or acquired CNS myelin disorders, such as multiple sclerosis and related acquired demyelinating processes, infectious and post-infectious white matter damage, toxic injuries and non-genetic vascular insults (Vanderver et al 2015a). Clinical manifestations Presentation and course The clinical approach includes getting the appropriate history, which comprises determining the mode of inheritance, followed by both general and neurologic examinations and a detailed examination of the brain with MRI and sometimes CT brain scans. The first clue to the diagnosis of a leukodystrophy should be determination of the mode of inheritance. This is difficult in a case wherein only 1 person in the family is affected. Such a sporadic case is most often observed in autosomal recessive inheritance but also in de novo autosomal dominant mutations (Prust et al 2011). An X-linked or mitochondrial disorder cannot be excluded in such cases. History of difficulty walking, ataxia, spasticity, visual impairment, seizures, and developmental delay or cognitive decline may be elicited. Hereditary diffuse leukoencephalopathy with spheroids and pigmentary orthochromatic leukodystrophies are adult onset leukodystrophies that typically present with cognitive and frontal lobe-based behavioral symptoms and signs months before motor deficits develop (Alturkustani et al 2015). The age of onset is key to differentiating between various leukodystrophies as some occur only in adults. However, many leukodystrophies, such as Alexander disease, can develop at any age (Prust et al 2011). History of acute deterioration, especially during stresses such as fever, suggests childhood ataxia and central hypomyelination/vanishing white matter (Schiffmann et al 1994). The general examination is important, especially in children and adolescents. Growth is often delayed in systemic disorders such as mitochondrial diseases; head circumference may be small in patients with Krabbe disease or megalencephalic in those with Canavan disease, Alexander disease, or megalencephalic leukoencephalopathy with subcortical cysts. A complete eye examination is important to look for the presence of cataract in some leukodystrophies, and optic atrophy is very common in white matter diseases but is conspicuously absent in some. The retina may show vascular retinal abnormalities as seen in cerebroretinal microangiopathy with calcifications and cysts (Polvi et al 2012); a cherry red spot may be present in patients with GM1 or GM2 gangliosidosis. Examination of the mouth can reveal a variety of teeth abnormalities and suggest 4H syndrome (Timmons et al 2006). Examination of the extremities may reveal xanthomas in cerebrotendinous xanthomatosis (Mignarri et al 2011). Examination of the skin may show increased skin pigmentation that suggests adrenal insufficiency and points towards X-linked adrenoleukodystrophy (Parikh et al 2015); ichthyosis would suggest the diagnosis of Sjögren-Larsson syndrome (Fuijkschot et al 2012). Neurologic examination in a patient with developmental delay may show abnormal eye movements, such as absence of smooth pursuit in 4H syndrome. Nystagmus and other eye movement control difficulties can be seen when the cerebellum or its pathways are affected. Palatal myoclonus is typical for juvenile Alexander disease (Hirayama et al 2008). The most common neurologic abnormalities seen in patients with leukodystrophies are some combination of spasticity and cerebellar ataxia. This can affect all 4 extremities or only the lower extremities with delays of independent walking or new onset of ataxia or a spastic gait. Dystonia may be present when the basal ganglia are involved as in HABC (van der Knaap et al 2007; Simons et al 2013; Pizzino et al 2014). Tendon reflexes are usually increased, but decreased ankle reflexes compared to knee jerks suggest the presence of a peripheral neuropathy that can be subtle with normal nerve conduction velocity (Timmons et al 2006). Sensory examination is typically grossly normal, but vibration perception is often reduced, especially when the disease process also affects peripheral nerves (Mochel et al 2012). Neuroimaging. Neuroimaging is key to the diagnosis of a leukodystrophy. By definition, in leukodystrophies, on MRI, T2-weighted signal hyperintensity in the white matter must be present, but T1-weighted signal may be variable (Schiffmann and van der Knaap 2009; Vanderver et al 2014). Iso- or hyperintense T1 signal is consistent with a hypomyelinating leukodystrophy.{embed="pagecomponents/media_embed" entry_id="10685"}{embed="pagecomponents/media_embed" entry_id="10686"} Other myelin pathologies, including demyelinating leukodystrophies, cause hypointense T1 signal. An algorithm based on MRI features has been constructed and is already used in many clinical settings (Schiffmann and van der Knaap 2009; Vanderver et al 2013).{embed="pagecomponents/media_embed" entry_id="10687"}{embed="pagecomponents/media_embed" entry_id="10688"} It should be stressed that although the pattern on the MRI is an extremely valuable diagnostic tool, it does not necessarily represent the actual pathological process; that is, a hypomyelinating pattern on the MRI does not imply an actual hypomyelination as in Pelizaeus-Merzbacher disease (Hobson and Garbern 2012). In 4H syndrome, for example, hypomyelination is a minor component of the neuropathological process (Vanderver et al 2013). An MRI pattern for a large cohort