Lysosomal Leukodystrophies Lysosomal Storage Diseases Associated With White Matter Abnormalities

Abstract

The leukodystrophies are a group of genetic metabolic diseases characterized by an abnormal development or progressive degeneration of the myelin sheath. The myelin is a complex sheath composed of several macromolecules covering axons as an insulator. Each of the leukodystrophies is caused by mutations in genes encoding enzymes that are involved in myelin production and maintenance. The lysosomal storage diseases are inborn disorders of compartmentalized cellular organelles with broad clinical manifestations secondary to the progressive accumulation of undegraded macromolecules within lysosomes and related organelles. The more than 60 different lysosomal storage diseases are rare diseases; however, collectively, the incidence of lysosomal storage diseases ranges just over 1 in 2500 live births. The majority of lysosomal storage diseases are associated with neurologic manifestations including developmental delay, seizures, acroparesthesia, motor weakness, and extrapyramidal signs. These inborn organelle disorders show wide clinical variability affecting individuals from all age groups. In addition, several of neurologic, also known as neuronopathic, lysosomal storage diseases are associated with some level of white matter disease, which often triggers the diagnostic investigation. Most lysosomal storage diseases are autosomal recessively inherited and few are X-linked, with females being at risk of presenting with mild, but clinically relevant neurologic manifestations. Biochemical assays are the basis of the diagnosis and are usually confirmed by molecular genetic testing. Novel therapies have emerged. However, most affected patients with lysosomal storage diseases have only supportive management to rely on. A better understanding of the mechanisms resulting in the leukodystrophy will certainly result in innovative and efficacious disease-modifying therapies.

Keywords: leukodystrophies; lysosomal diseases; lysosome; myelin.

Figure 1. Brain magnetic resonance imaging (MRI) of a patient with metachromatic leukodystrophy (MLD).

A 7-year old female who had one-year history of progressive ataxia, cognitive impairment and dysarthria which started approximately 18 months before the brain MRI was performed. She was diagnosed with the juvenile form of MLD. Sequences of fluid attenuated inversion recovery (FLAIR; A-C) and T2-weighted turbo spin echo (T2W_TSE; D-F) of transverse sections are shown. (A) The brain MRI shows typical widespread hyperintensity signals affecting the entire centrum semiovale of both hemispheres, frontal, parietal and occipital regions extending bilaterally to the temporal white matter. In panel B, the white-arrow shows subcortical U-fibers in the L frontal lobe, that are initially spared in MLD. (C and F) Brainstem shows small scattered areas of punctate high-signal representing also white matter demyelination, mostly in the thalami and subthalamic regions in the T2W and FLAIR sequences.

Figure 2. Glycosphingolipidosis and white matter alterations.

(A-C) This 8.7-year-old girl diagnosed with the juvenile clinical form of GM2 gangliosidosis (Sandhoff variant). She presented with severe cognitive dysfunction, dysarthria, ataxia, muscle wasting, urinary and fecal incontinence at baseline. Psychiatric problems included visual and auditory hallucinations and agitation. She was fully dependent for feeding, bathing, toileting and ambulation when she underwent a brain MRI. (A and B) The brain MRI transverse section showed normal ventricular size with mild FLAIR signal intensity of white matter around the posterior trigones in occipital regions (arrows) as shown in panels A (T2W_TSE) and B (FLAIR). (C) Moderate atrophy of corpus callosum is noticeable as well as moderate diffuse atrophy of cerebellum with a brighter FLAIR signal of globous pallidus. (D-F) A 50-year old man diagnosed with Fabry disease with history of chronic renal disease (stage II), hypertrophic cardiomyopathy, progressive hearing loss and chronic pain and hypohidrosis. Both transverse T2W_TSE (D) and FLAIR (E) sequences show hyperintensity signals in the frontal and occipital periventricular regions. (F) The magnetic resonance arteriography (MRA) revealed dolichoectasia with internal carotids, basilar and middle cerebral arteries as typically observed in Fabry disease. Rt.MCA, right middle cerebral artery; Lt.MCA, left middle cerebral artery; Rt.ICA, right internal carotid artery; Lt.ICA, left internal carotid artery; Bas.A, basilar artery.