This book is one of our contemporary medical bibles. It needs no introduction; those who have frequent need of it know it very well, and those who use it less often seek it out on the library shelf when problems arise. The book is truly encyclopedic. Everything relevant discovered during the six-year intervals between publication finds its way into these pages. By today's standards, its 1,778 closely packed small-print pages are a bargain. The mutant gene is both hero and villain in this book. It is reponsible for the biochemical abnormality that results in disease, no matter how rare a given abnormality may be. By the same token, however, it is truly an experiment of nature, shedding light on fundamental metabolic sequences and biologic mechanisms. This volume, more than most, explains the contributions of the laboratory to clinical medicine. Each chapter seems to have been rewritten, so that the exciting

The Metabolic Basis Of Inherited Disease.

Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include other lipidoses; idiopathic neonatal hepatitis and other causes of cholestatic icterus should be considered in neonates, and conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults. Symptomatic management of patients is crucial. A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. The prognosis largely correlates with the age at onset of the neurological manifestations.

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Niemann-Pick disease type C

Niemann-Pick disease type C (NPC) is an autosomal recessive neurovisceral lipid storage with a wide spectrum of clinical phenotypes. At the cellular level, the disorder is characterized by accumulation of unesterified cholesterol and glycolipids in the lysosomal/late endosomal system. Approximatively 95% of patients have mutations in the NPC1 gene (mapped at 18q11) which encodes a large membrane glycoprotein primarily located to late endosomes. The remainder have mutations in the NPC2 gene (mapped at 14q24.3) which encodes a small soluble lysosomal protein with cholesterol-binding properties. The identical biochemical patterns observed in NPC1 and NPC2 mutants suggest that the two proteins function in a coordinate fashion. Identification of mutations revealed a complex picture of molecular heterogeneity, allowing genotype - phenotype correlations for both genes and providing insights into structure - function relationships for the NPC1 protein. Although a whole body of evidence suggests that the NPC1 and NPC2 proteins are involved in the cellular postlysosomal/late endosomal transport of cholesterol, glycolipids and other cargo, their precise functions and relationship remain unclear and are currently the subject of intense investigation. These studies, conducted in various models, should ultimately lead to a better understanding of the pathophysiology of NPC and new therapeutic approaches.

/pdf/niemann-pick-disease-type-c-3us3yesih9.pdf

Niemann-Pick disease type C.

Intracellular cholesterol transport

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(08)61522-6.pdf

Phenotype, diagnosis, and treatment of Gaucher's disease.

Analysis of the neurologic symptomatology in 22 patients with Niemann-Pick disease type C revealed 3 phenotypes: (1) an early-onset, rapidly progressive form associated with severe hepatic dysfunction and psychomotor delay during infancy and later with supranuclear vertical gaze paresis, ataxia, marked spasticity, and dementia; (2) a delayed-onset, slowly progressive form heralded by the appearance, usually in early childhood, of mild intellectual impairment, supranuclear vertical gaze paresis, and ataxia, and later associated with dementia and, variably, seizures and extrapyramidal deficits; (3) a late-onset slowly progressive form distinguished from the 2nd pattern by later age of onset (adolescence or adulthood) and a much slower rate of progression. The existence of the 1st and 2nd phenotypes within the same sibship suggests that they are variant expressions of the same clinicopathologic disorder. Niemann-Pick disease type C should be considered not only in infants and children who present with organomegaly and a progressive neurodegenerative course, but also in adolescents and adults who have insidiously progressive neurologic dysfunction and only slight organomegaly. Associated with the disease is a marked deficiency in the ability of cultured fibroblasts to esterify exogenously supplied cholesterol. Assay of this deficiency is particularly useful for confirming the diagnosis in patients with atypical presentation.

Clinical spectrum of Niemann‐Pick disease type C

Type 3 neuronopathic Gaucher9s disease (GD3) is phenotypically heterogeneous. In many GD3 patients, progressive myoclonus and dementia dominate the illness, with death secondary to progressive CNS disease. We have designated this group as GD3a. We studied 14 children with Gaucher9s disease, isolated horizontal supranuclear gaze palsy, and aggressive systemic disease, and designated this group as GD3b. In comparison with 13 children with type 1 non-neuronopathic Gaucher9s disease, the GD3b children presented earlier, and were shorter, underweight, and more prone to cardiopulmonary, hepatic, and skeletal complications. One-half of the children died in childhood or adolescence of systemic complications. Patients with at least one copy of the mutation that causes substitution of asparagine for serine at amino acid 370 of glucocerebrosidase did not develop neurologic signs. Patients homoallelic for the mutation causing substitution of leucine for proline at position 444 had severe systemic disease; neurologic signs were frequently, but not invariably, present. Early diagnosis and timely enzyme replacement therapy promise to improve the prognosis in GD3b.

Isolated horizontal supranuclear gaze palsy as a marker of severe systemic involvement in Gaucher's disease

Analysis of the temporal sequence of neurologic events, neurophysiologic abnormalities, and longevity in 36 Niemann-Pick type C patients revealed two clinical subgroups with five stages of severity within each group. Patients with a preschool onset (group I; n = 18) had a higher mortality than did patients with a school-age onset (group II; n = 18). An asymptomatic phase (stage 0) was defined by biochemical and histopathologic evidence of disease. The initial manifestations of stage 1 were a movement disorder (group I) and cognitive difficulties (group II) accompanied by impaired vertical saccadic eye movements and abnormal acoustic reflexes. Stage 2 was characterized by the sequential occurrence of vertical supranuclear gaze palsy (VSGP), cognitive difficulties, and dysarthria in group I and a movement disorder, VSGP, and dysarthria in group II. Pyramidal tract signs and abnormal brainstem auditory evoked responses defined stage 3 in both groups. Stage 4 culminated in a nonambulant, vegetative state.

A. Pikus

Papers

Clinical spectrum of Niemann‐Pick disease type C

Isolated horizontal supranuclear gaze palsy as a marker of severe systemic involvement in Gaucher's disease

A clinical staging classification for type C Niemann-Pick disease