1/191. The rontgenographic findings in the acute neuronopathic form of Niemann-Pick disease. The rontgenographic changes are described in two patients with the acute neuronopathic form of Niemann-Pick disease. These consist of metaphyseal splaying, osteoporosis and the quadrate appearance of the lumbar vertebrae with relatively long pedicles. The parenchymatous involvement is manifested by interstitial lung changes, enlargement of liver, spleen and kidney and distended intestinal loops with an abnormal mucosal pattern associated with prolonged transit time of the contrast material. The differential diagnosis of the above changes is discussed. ( info) |
2/191. Biochemical, genetic and ultrastructural study of a family with the sea-blue histiocyte syndrome/chronic non-neuronopathic Niemann-Pick disease. Deficient leucocyte sphingomyelinase activity has been demonstrated in a patient with the sea-blue histiocyte syndrome. family studies revealed that two other cases previously diagnosed on clinical and histochemical criteria also had a pronounced diminution of sphingomyelinase activity. Both parents of the affected individuals were carriers of the disease as indicated by sphingomyelinase activity intermediate between normal and diseased subjects. Additional heteroxygous carriers were found among the siblings and other relatives of the patients. This family study supports further the hypothesis that the sea-blue histiocyte syndrome and chronic Niemann-Pick (Type B) disease are the same. ( info) |
3/191. MRI in an unusually protracted neuronopathic variant of acid sphingomyelinase deficiency. MRI was performed in two siblings with the neuropathic sphingomyelinase deficiency caused by identical mixed heterozygosity in the structural acid sphingomyelinase gene. The clinical phenotype of the cases is unique in showing a rather protracted course, both having reached the fourth decade. Pronounced cerebellar and mild supratentorial atrophy was seen on MRI in both siblings, in contrast to their strikingly different clinical status. One has no overt neurological deficit, while the second had neocerebellar symptoms and signs, nystagmus and cranial nerve palsies for some years. The MRI findings, together with the cherry-red spot in the ocular fundus, ultrastructurally proved storage in cutaneous nerve schwann cells and the histopathologically proven brain neuronal storage in a third sibling who died after a relatively rapid course dominated by fatal visceral storage, is evidence that a remarkably restricted neuropathology can be caused by this enzymopathy. ( info) |
| bone marrow transplantation (BMT) has been used for a wide variety of lysosomal storage diseases with encouraging results. We report a 3-year 5-month-old girl with Niemann-Pick type C disease (NPC) who received an allogeneic BMT. The patient presented with repeated lower respiratory tract infections, hepatosplenomegaly, failure to thrive, and developmental delay. Chest computed tomography (CT) revealed diffuse interstitial lung infiltration. Bone marrow and liver biopsies revealed abundant lipid-filled foamy macrophages. skin fibroblast sphingomyelinase assay revealed partial deficiency. The ability of her skin fibroblasts to esterify cholesterol was very low, and the cells stained brightly for free cholesterol. She received BMT from a healthy HLA-identical male sibling donor at the age of 2 year 6 months. Full engraftment was evidenced by repeated bone marrow sex chromosome studies. Regression of the hepatosplenomegaly, markedly reduced foamy macrophage infiltration in bone marrow, and decreased interstitial lung infiltration was noted 6 months after BMT. Her neurological status, however, deteriorated. Follow-up magnetic resonance image (MRI) revealed progressive, diffuse brain atrophy. We conclude that resolution occurred in the liver, spleen, bone marrow and lung following successful engraftment. Such a response is remarkable since the underlying problem involves a membrane receptor for cholesterol. This positive response might be due to replacement of the monocyte-phagocytic system or it may imply the existence of cross-correction in the NPC membrane receptor defect by BMT approach. Since BMT did not halt the neurological deterioration, it is unlikely to be an adequate treatment for NPC. ( info) |
5/191. Niemann-Pick disease type C: two cases and an update. We describe two patients with juvenile-onset Niemann-Pick disease type C (NPC) to illustrate the variable neurologic features of this condition. One presented with hypersplenism at age 10 and was misdiagnosed with gaucher disease. He developed complex partial seizures in his teens but remained otherwise neurologically asymptomatic until his mid 30s. At age 45, he had mild dementia and dysarthria, vertical supranuclear ophthalmoplegia, axonal sensorimotor polyneuropathy, and cerebellar ataxia. The second patient presented with rapidly progressive dystonia at age 8, and mild hepatosplenomegaly, vertical supranuclear ophthalmoplegia, severe behavioral disorder, and dementia by age 14. The diagnosis of NPC was based on deficient cholesterol esterification and excessive lysosomal filipin staining in cultured skin fibroblasts. Current notions about diagnosis and pathogenesis of NPC are reviewed. ( info) |
6/191. SSCP analysis by RT-PCR for the prenatal diagnosis of Niemann-Pick disease type C. The molecular prenatal diagnosis of Niemann-Pick disease type C (NPC) is presented. The proband with a late infantile type of NPC was a compound heterozygote of a paternal missense mutation, T529G, and a maternal 2 bp deletion at nt 350 of the NPC1 gene. These mutations were detected by single-strand conformation polymorphism (SSCP) analysis of RT-PCR products. When the proband was aged 4 years 3 months, prenatal diagnosis for the second child was performed using both biochemical and molecular methods. SSCP analysis for the parental mutations using cDNA from cultured amniotic fluid cells revealed the absence of both mutations and the fetus was diagnosed as being unaffected. This diagnosis was supported by a normal level of cholesterol esterification using cultured amniotic fluid cells. After the child's birth, when he was 21 months old, the diagnosis was confirmed by SSCP analysis of genomic DNAs of his family. This analysis also revealed a unique variation of intron 13, IVS13 753-758 del TTTTTT, that was shared only by the proband and the father, and was suspected as being linked to the T529G missense mutation. A combination of both biochemical and molecular analyses is very useful and reliable for prenatal diagnosis of Niemann-Pick disease type C. ( info) |
7/191. Pulmonary involvement in Niemann-Pick disease: case report and literature review. Niemann-Pick disease (NPD) is a rare, inherited, autosomal recessive, lipid storage disease. The pathognomonic intracellular accumulation of sphingomyelin results in the production and accumulation of 'foam cells'. Interstitial lung disease is a rare manifestation of NPD. We present the case of a 48-year-old white female with NPD involving the lungs, liver and spleen. The chest radiograph showed bilateral, predominantly basal reticulonodular infiltrates and serial pulmonary function tests over a period of years showed preserved expiratory airflow and a severely decreased diffusion capacity for carbon monoxide (DLCO). In view of her visceral involvement, lack of neurological symptoms and survival into adulthood, we believe our patient represents a case of type B NPD. In this type of NPD, aside from prominent hepatosplenomegaly and sexual immaturity, significant pulmonary infiltration with 'Pick cells' has been reported. To date, no therapeutic modality has been shown to alter the natural history of this disease, which results in progressive debilitation and death. This case is unique in that it provides the longest physiological follow-up in the literature, and provides data on the natural history of pulmonary involvement in NPD. ( info) |
8/191. Type A Niemann-Pick disease. Niemann-Pick disease (NPD) represents a type of lysosomal storage diseases in which sphingomyelin accumulates in the histocytes and reticuloendothelial cells of the spleen, liver, lymph nodes, bone marrow and central nervous system. We report a child with massive hepatosplenomegaly, lymphadenopathy, mental retardation and widespread papulonodular lesions. His clinical features conform to the type A subgroup of NPD. ( info) |
9/191. Isolated splenomegaly as the presenting feature of Niemann-Pick disease type C. WE DESCRIBE FOUR patients WITH NIEMANN: Pick disease type C (NPC), in whom the presentation was isolated splenic enlargement; this remained the only abnormality for a number of years. Diagnosis can be suggested by either finding abnormal storage material in a tissue biopsy specimen or by showing a modest elevation in plasma chitotriosidase activity. In patients with suggestive abnormalities, filipin staining of a skin fibroblast sample should confirm the abnormality in cholesterol trafficking. Formal esterification studies and mutation analysis should also be performed, especially if prenatal testing is to be performed in subsequent pregnancies. If the diagnosis is not considered and established, the family are at risk of having further affected children. Investigation of patients with isolated splenomegaly is not complete until NPC has been excluded. ( info) |
10/191. Sphingomyelin storage in a patient with myoclonus epilepsy as a main clinical symptom -- a varient in Niemann-Pick disease type C. A patient with myoclonus epilepsy as a main clinical symptom was histopathologically diagnosed as a generalized sphingolipidosis. It was found that both sphingomyelin and globoside I fairly increased in kidney, heart, lung and liver. While, only sphingomyelin was found to increase in cerebral gray and white matters and cerebellum, but other lipids were within the normal range. Sphingomyelin accounted for 22% of the total phospholipids especially in cerebellum. No cholesterol ester and ganglioside GM2 or asialo GM2 were in particular found in the brain. Fatty acid compositions of phospholipids, glycosphingolipids and gangliosides were found to be normal. Judging from the sphingomyelin storage not only in visceral organs but also in brain tissues, it was proposed that this disease might be a variant in Niemann-Pick disease Type C, although an enzymatic assay of sphingomyelinase still remains. ( info) |