Metachromatic leukodystrophy: a scoring system for brain MR imaging observations.

BACKGROUND AND PURPOSE: Metachromatic leukodystrophy (MLD) is a devastating demyelinating disease for which novel therapies are being tested. We hypothesized that MR imaging of brain lesion involvement in MLD could be quantified along a scale. MATERIALS AND METHODS: Thirty-four brain MR images in 28 patients with proved biochemical and genetic defects for MLD were reviewed: 10 patients with late infantile, 16 patients with juvenile, and 2 patients with adult MLD. All MR images were reviewed by experienced neuroradiologists and neurologists (2 readers in Germany, 2 readers in the United States) for global disease burden, as seen on the T2 and fluid-attenuated inversion recovery images. A visual scoring method was based on a point system (range, 0-34) derived from the location of white matter involvement and the presence of global atrophy, analogous to the scoring system developed for adrenoleukodystrophy. The readers were blinded to the neurologic findings. RESULTS: Thirty-three of 34 MR images showed confluent T2 hyperintensities of white matter. The inter-rater reliability coefficient was 0.988. Scores between readers were within 2 points of each other. Serial MR imaging studies in 6 patients showed significant progressive disease in 3 patients (initial score average, 4; mean follow-up, 24.3) and no change or 1 point progression in 3 patients (initial score average, 12; mean follow-up, 12.66). Projection fibers and the cerebellum tended to be involved only in advanced stages of disease. CONCLUSIONS: The MLD MR severity scoring method can be used to provide a measure of brain MR imaging involvement in MLD patients.

Rapidly progressive vanishing white matter disease in a child with previously inconspicuous brain MRI.

In this pediatric case of vanishing white matter disease with early onset, rapidly progressive course, and fatal outcome, the white matter vanishing process in patient was for the first time documented morphologically in detail: An initial magnetic resonance imaging documented a normal appearing brain maturation. Rapid progressive brain lesions initiated morphologically DE NOVO in the former well myelinated deep white matter were observed six months later after disease onset, including concentric ongoing signs of restricted proton diffusion cytotoxic edema on diffusion weighted imaging. Cyst-like defects at the lesion center of the deep white matter were detected more clearly on MRI ten months later. A pathomechanism like tumor necrosis factor induced oligodendrocyte apoptosis and primary demyelination was postulated. The case demonstrates that in the presence of clinically progressive symptoms, the development of VWM is possible even if first MRI findings are negative.

LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.

In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.

Slow progression of juvenile metachromatic leukodystrophy 6 years after bone marrow transplantation.

Metachromatic leukodystrophy refers to a group of genetic neurologic diseases caused by deficiencies of the enzyme arylsulfatase A and the resulting accumulation of sulfatides in white matter. Bone marrow transplantation has been advocated as a treatment in an attempt to correct the enzyme deficiency. Such a transplant was performed in 1991 in a 16-year-old girl with a form of late juvenile metachromatic leukodystrophy caused by a homozygous P426L mutation in the arylsulfatase A gene. Engraftment was prompt and resulted in constant enzymatic normalization of circulating lymphocytes. The elevated urinary excretion of sulfatides remained unaffected. Clinical findings up until transplantation consisted of gait disturbances, impairment of cognitive functioning, and deterioration in school performance over several years. During a 6-year follow-up period, the patient's condition was subject to major fluctuations but, on the whole, findings showed slow neurologic and neurophysiologic deterioration. The clinical course observed after bone marrow transplantation probably more or less reflects the natural course expected in this form of late-onset metachromatic leukodystrophy.

Brittle cornea syndrome: an heritable connective tissue disorder distinct from Ehlers-Danlos syndrome type VI and fragilitas oculi, with spontaneous perforations of the eye, blue sclerae, red hair, and normal collagen lysyl hydroxylation.

We report a patient with the characteristic features of the brittle cornea syndrome, a rare, autosomal recessively inherited disorder, namely brittle corneae, blue sclerae, and red hair. The patient also showed joint hyperextensibility, a soft skin, and dysplastic auricles with unusually soft cartilage. Phenotypically, the disorder bears a certain resemblance to fragilitas oculi and the type VI (ocular) form of the Ehlers-Danlos syndrome, two conditions which are, themselves, not readily distinguishable. However, the hydroxylysine content of dermal collagen was normal, as was the activity of lysyl hydroxylase in cultured dermal fibroblasts, thus supporting the distinction of the brittle cornea syndrome as an independent entity. No abnormality was discernible in types I or III collagens synthesised by cultured fibroblasts, but electron microscopy revealed dramatic ultrastructural alterations in dermis in that distributed over its whole thickness were 20-60 microns wide "holes" or fibre-free spaces, filled with an amorphous material.