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Abstract:Our results demonstrate that gallbladder involvement is the rule rather than the exception in MLD. The high prevalence of hyperplastic polyps, a known precancerous condition, and one death from gallbladder carcinoma at a young age suggest that MLD predisposes to neoplastic gallbladder abnormalities. As novel therapies for this patient group are emerging leading to increased life expectancy, we recommend screening for gallbladder abnormalities by ultrasound in order to prevent early death.
“…In more severe cases, involvement of the cerebellar white matter, basal nuclei and thalami can also occur. Accumulation of sulfatides also occurs in visceral organs, most often the gallbladder [ 258 ]. Fig.…”
Section: Pathology and Mechanisms Of Genetic White Matter Disorders: mentioning
confidence: 99%
“…In the gallbladder, metachromatic stroma macrophages often coexist with intestinal metaplasia of the epithelium, hyperplasia of the muscle wall and papillomatosis. Occurrence of gallbladder carcinoma has been reported in young MLD patients, suggesting that sulfatide accumulation at this site may predispose to development of neoplasia [ 258 ].…”
Section: Pathology and Mechanisms Of Genetic White Matter Disorders: mentioning
Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed a tremendous increase in the number of defined leukodystrophies also owing to a diagnostic approach combining magnetic resonance imaging pattern recognition and next generation sequencing. Knowledge on white matter physiology and pathology has also dramatically built up. This led to the recognition that only few leukodystrophies are due to mutations in myelin- or oligodendrocyte-specific genes, and many are rather caused by defects in other white matter structural components, including astrocytes, microglia, axons and blood vessels. We here propose a novel classification of leukodystrophies that takes into account the primary involvement of any white matter component. Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin (hypomyelinating and demyelinating leukodystrophies, leukodystrophies with myelin vacuolization); astrocytopathies; leuko-axonopathies; microgliopathies; and leuko-vasculopathies. Following this classification, we illustrate the neuropathology and disease mechanisms of some leukodystrophies taken as example for each category. Some leukodystrophies fall into more than one category. Given the complex molecular and cellular interplay underlying white matter pathology, recognition of the cellular pathology behind a disease becomes crucial in addressing possible treatment strategies.
“…In more severe cases, involvement of the cerebellar white matter, basal nuclei and thalami can also occur. Accumulation of sulfatides also occurs in visceral organs, most often the gallbladder [ 258 ]. Fig.…”
Section: Pathology and Mechanisms Of Genetic White Matter Disorders: mentioning
confidence: 99%
“…In the gallbladder, metachromatic stroma macrophages often coexist with intestinal metaplasia of the epithelium, hyperplasia of the muscle wall and papillomatosis. Occurrence of gallbladder carcinoma has been reported in young MLD patients, suggesting that sulfatide accumulation at this site may predispose to development of neoplasia [ 258 ].…”
Section: Pathology and Mechanisms Of Genetic White Matter Disorders: mentioning
Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed a tremendous increase in the number of defined leukodystrophies also owing to a diagnostic approach combining magnetic resonance imaging pattern recognition and next generation sequencing. Knowledge on white matter physiology and pathology has also dramatically built up. This led to the recognition that only few leukodystrophies are due to mutations in myelin- or oligodendrocyte-specific genes, and many are rather caused by defects in other white matter structural components, including astrocytes, microglia, axons and blood vessels. We here propose a novel classification of leukodystrophies that takes into account the primary involvement of any white matter component. Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin (hypomyelinating and demyelinating leukodystrophies, leukodystrophies with myelin vacuolization); astrocytopathies; leuko-axonopathies; microgliopathies; and leuko-vasculopathies. Following this classification, we illustrate the neuropathology and disease mechanisms of some leukodystrophies taken as example for each category. Some leukodystrophies fall into more than one category. Given the complex molecular and cellular interplay underlying white matter pathology, recognition of the cellular pathology behind a disease becomes crucial in addressing possible treatment strategies.
“…Acute GVHD grade II-IV at day 100 was diagnosed and graded according to published criteria. 14 Chronic GVHD at 5 years was graded according to standard criteria 15 16,17 and adrenal insufficiency for patients with X-ALD (as reported by local clinicians).…”
Leukodystrophies (LD) are devastating inherited disorders leading to rapid neurological deterioration and premature death. Hematopoietic stem cell transplantation (HSCT) can halt disease progression for selected LD. Cord blood is a common donor source for transplantation of these patients because it is rapidly available and can be used without full HLA matching. However, precise recommendations allowing care providers to identify patients who benefit from HSCT are lacking. In this study, we define risk factors and describe the early and late outcomes of 169 patients with globoid cell leukodystrophy, X-linked adrenoleukodystrophy, and metachromatic leukodystrophy undergoing cord blood transplantation (CBT) at an European Society for Blood and Marrow Transplantation center or at Duke University Medical Center from 1996 to 2013. Factors associated with higher overall survival (OS) included presymptomatic status (77% vs 49%; = .006), well-matched (≤1 HLA mismatch) CB units (71% vs 54%; = .009), and performance status (PS) of >80 vs <60 or 60 to 80 (69% vs 32% and 55%, respectively; = .003). For patients with PS≤60 (n = 20) or 60 to 80 (n = 24) pre-CBT, only 4 (9%) showed improvement. Of the survivors with PS>80 pre-CBT, 50% remained stable, 20% declined to 60 to 80, and 30% to <60. Overall, an encouraging OS was found for LD patients after CBT, especially for those who are presymptomatic before CBT and received adequately dosed grafts. Early identification and fast referral to a specialized center may lead to earlier treatment and, subsequently, to improved outcomes.
“…Gall bladder involvement including polyposis, sludge, gallstone, cholecystitis, papillomatosis, and small or enlarged gallbladder is a well-known manifestation and has been more commonly described in juvenile or adult-onset MLD. [11][12][13] These symptoms may be due to the prolonged contact of gallbladder epithelium with sulfatides accumulating in bile during the course of the disease. Although gall bladder polyposis can be an initial manifestation of MLD, it has never been described in reported saposin B-deficient MLD patients.…”
Metachromatic leukodystrophy (MLD) is a rare sphingolipid storage disorder caused by arylsulfatase A (ARSA) deficiency, resulting in central and peripheral demyelination. However, an uncommon form of MLD caused by saposin B deficiency is also described (around 10 mutations reported till date). MLD is a systemic disorder affecting the central and peripheral nervous system, gall bladder, and kidneys. Acute flaccid paralysis as the initial clinical presentation is previously known in ARSA-deficient MLD. Hereby, we report a child with acute flaccid paralysis with brain magnetic resonance imaging showing nonspecific periventricular leukodystrophy. He had progressive cognitive decline with gall bladder polyposis. ARSA levels were within normal limits. Leukodystrophy gene panel revealed a homozygous pathogenic deletion (Lys227del variant) in prosaposin (PSAP) gene. Hence, a final diagnosis of saposin B–deficient MLD was established. The index case highlights the importance of clinical and electrophysiological clues in the diagnosis of such atypical presentations of MLD.
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