A number sign (#) is used with this entry because Niemann-Pick disease type C2 (NPC2) is caused by homozygous mutation in the NPC2 gene (601015) on chromosome 14q24. Description Niemann-Pick type C (NPC) disease is an autosomal recessive lipid storage disorder characterized by progressive neurodegeneration. Approximately 95% of cases are caused by mutations in the NPC1 gene (607623), referred to as type C1 (257220); 5% are caused by mutations in the NPC2 gene (601015), referred to as type C2. The clinical manifestations of types C1 (257220) and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes (summary by Vance, 2006). Clinical Features Vanier et al. (1996) reported 5 patients with NPC2.
A number sign (#) is used with this entry because Niemann-Pick disease type C1 and Niemann-Pick disease type D, also known as the Nova Scotian type, are caused by homozygous or compound heterozygous mutation in the NPC1 gene (607623) on chromosome 18q11. Description Niemann-Pick type C (NPC) disease is an autosomal recessive lipid storage disorder characterized by progressive neurodegeneration. Approximately 95% of cases are caused by mutations in the NPC1 gene, referred to as type C1; 5% are caused by mutations in the NPC2 gene (601015), referred to as type C2 (607625). The clinical manifestations of types C1 and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes (summary by Vance, 2006). Historically, Crocker (1961) delineated 4 types of Niemann-Pick disease: the classic infantile form (type A; 257200), the visceral form (type B; 607616), the subacute or juvenile form (type C), and the Nova Scotian variant (type D).
Summary Clinical characteristics. Niemann-Pick disease type C (NPC) is a lipid storage disease that can present in infants, children, or adults. Neonates can present with ascites and severe liver disease from infiltration of the liver and/or respiratory failure from infiltration of the lungs. Other infants, without liver or pulmonary disease, have hypotonia and developmental delay. The classic presentation occurs in mid-to-late childhood with the insidious onset of ataxia, vertical supranuclear gaze palsy (VSGP), and dementia. Dystonia and seizures are common. Dysarthria and dysphagia eventually become disabling, making oral feeding impossible; death usually occurs in the late second or third decade from aspiration pneumonia.
Niemann-Pick disease type C (NP-C) is a lysosomal lipid storage disease (see this term) characterized by variable clinical signs, depending on the age of onset, such as prolonged unexplained neonatal jaundice or cholestasis, isolated unexplained splenomegaly, and progressive, often severe neurological symptoms such as cognitive decline, cerebellar ataxia, vertical supranuclear gaze palsy (VSPG), dysarthria, dysphagia, dystonia, seizures, gelastic cataplexy, and psychiatric disorders.
A rare metabolic disorder for which two forms have been described. Lack of activity of the erythrocyte isoform of adenosine monophosphate (AMP) deaminase has been described in subjects with low plasma uric acid levels without obvious clinical relevance and will not be described further. Myoadenylate deaminase deficiency is an inherited disorder of muscular energy metabolism with a lack of AMP deaminase activity in skeletal muscle. It is characterised by exercise-induced muscle pain, cramps and/or early fatigue. Epidemiology About 1-2% of the Caucasian population carries the genetic defect causing myoadenylate deaminase deficiency, but only a minority of carriers develop symptoms. The prevalence is unknown but several hundred patients with the disorder have been reported in case reports and patient series.
Diffuse panbronchiolitis (DPB) is a rare condition characterized by inflammation of the small airways of the lungs (bronchiolitis) and chronic sinusitis. It mainly occurs among the Japanese but has been reported in other populations. Symptoms typically develop anywhere from the teenage years to the fifth decade of life and are slowly progressive over months to years. Common symptoms include chronic sinusitis, a productive cough (producing mucus), breathlessness with exertion, wheezing, and weight loss (especially as symptoms worsen). The exact cause of DPB is not known, but a variety of genetic, environmental, and systemic factors appear to contribute to the condition.
Diffuse panbronchiolitis is a rare chronic inflammatory obstructive pulmonary disease primarily affecting the respiratory bronchioles throughout both lungs and inducing sinobronchial infection. Onset occurs in the second to fifth decade of life and manifests by chronic cough, exertional dyspnea, and sputum production. Most patients also have chronic paranasal sinusitis
Description Diffuse panbronchiolitis (DPB) is a rare chronic inflammatory obstructive pulmonary disease primarily affecting the respiratory bronchioles. 'Diffuse' refers to the distribution of the lesions throughout both lungs, and 'pan-' refers to the involvement of inflammation in all layers of the respiratory bronchioles. Onset of the disorder occurs in the second to fifth decade of life, and is clinically manifest by chronic cough, exertional dyspnea, and sputum production. Most patients also have chronic paranasal sinusitis. If untreated, the disorder progresses to bronchiectasis, respiratory failure, and death (summary by Poletti et al., 2006). Clinical Features Yamanaka et al. (1969) first described a chronic airway disease in Japan.
For a phenotypic description and a discussion of genetic heterogeneity of progressive supranuclear palsy (PSP), see PSNP1 (601104). Clinical Features De Yebenes et al. (1995) studied a 5-generation Spanish family in which progressive supranuclear palsy was transmitted as an autosomal dominant trait. The proband had the classic presentation of this disorder beginning with axial rigidity, slowness of movement, and gait difficulty. Over the course of 2 years he progressed to complete vertical gaze palsy, axial dystonia, and retrocollis, as well as generalized severe akinesia. Postmortem examination demonstrated neuronal loss and atrophy of the brainstem, cerebellum, and diencephalon.
Progressive supranuclear palsy is a brain disorder that affects movement, vision, speech, and thinking ability (cognition). The signs and symptoms of this disorder usually become apparent in mid- to late adulthood, most often in a person's 60s. Most people with progressive supranuclear palsy survive 5 to 9 years after the disease first appears, although a few affected individuals have lived for more than a decade. Loss of balance and frequent falls are the most common early signs of progressive supranuclear palsy. Affected individuals have problems with walking, including poor coordination and an unsteady, lurching gait.
For a phenotypic description and a discussion of genetic heterogeneity of progressive supranuclear palsy (PSP), see PSNP1 (601104). Mapping Using a pooling-based genomewide association study of more than 500,000 SNPs in 288 patients with PSP and 344 age- and sex-matched controls, Melquist et al. (2007) identified candidate SNPs with large differences in allelic frequency by ranking all SNPs by their probe-intensity difference between cohorts. The MAPT H1 haplotype (see 157140) was strongly detected by this approach as was a second major locus (PSNP3) on chromosome 11p12-p11 that showed evidence of association at allelic (p less than 0.001), genotypic (p less than 0.001), and haplotypic (p less than 0.0001) levels and was narrowed to a single haplotype block containing the DNA damage-binding protein-2 (DDB2; 600811) and lysosomal acid phosphatase-2 (ACP2; 171650) genes. Since DNA damage and lysosomal dysfunction have been implicated in aging and neurodegenerative processes, Melquist et al. (2007) considered both genes to be viable candidates for conferring risk of disease.
A number sign (#) is used with this entry because of evidence that progressive supranuclear palsy-1 (PSNP1) is caused by heterozygous mutation in the gene encoding microtubule-associated protein tau (MAPT; 157140) on chromosome 17q21. Description Progressive supranuclear palsy (PSP) is the second most frequent cause of degenerative parkinsonism. In addition to parkinsonism, the clinical symptoms include early postural instability, supranuclear gaze palsy, and cognitive decline. Neuropathologically, the disorder is characterized by abundant neurofibrillary tangles, which differ in both distribution and composition from those associated with Alzheimer disease. In progressive supranuclear palsy, the tangles are primarily localized to subcortical regions and are found in both neurons and glia, whereas in Alzheimer disease they are more widespread, largely cortical, and limited to neurons.
A number sign (#) is used with this entry because of evidence that a form of atypical supranuclear palsy is caused by mutation in the microtubule-associated protein tau gene (MAPT; 157140). Clinical Features Mata et al. (1983) described 2 brothers and a sister with a 'new' Parkinson-dementia syndrome. The disorder, characterized also by ophthalmoparesis and pyramidal signs, came on in the third decade and progressed for several years. Kyphoscoliosis was present in all 3 sibs. Examination of the brain in the sister, who died at age 31 years, showed neurofibrillary degeneration of the hippocampus, basal ganglia and brainstem nuclei. The parents were not related. The authors suggested that the disorder most closely resembled the Parkinson-dementia complex of Guam (105500) but could be distinguished by the lack of Chamorro descent (a dubious argument) and the earlier age of onset.
Classical progressive supranuclear palsy, also known as Richardson's syndrome, is the most common clinical variant of progressive supranuclear palsy (PSP; see this term), a rare late-onset neurodegenerative disease characterized by postural instability, progressive rigidity, supranuclear gaze palsy and mild dementia. Epidemiology The prevalence is conservatively estimated at about 1/16,600. Clinical description PSP usually manifests during the sixth or seventh decade of life with postural instability and falls, slowing of vertical saccadic eye movements and cognitive slowing. Progressively patients develop other eye abnormalities (dry and red eyes, blurred vision, spontaneous involuntary eyelid closure, photophobia), a dysexecutive cognitive syndrome with impulsivity, problems in speech (slow speech) and a supranuclear gaze palsy and difficulties in swallowing. The disease is characterized neuropathologically by gliosis with astrocytic plaques, accumulation of tau-immunoreactive neurofibrillary tangles and neuronal loss in specific brain areas, especially in the subthalamic nucleus and the substantia nigra.
Progressive supranuclear palsy (PSP) is a degenerative neurologic disease due to damage to nerve cells in the brain. Signs and symptoms vary but may include loss of balance; blurring of vision; problems controlling eye movement; changes in mood, behavior and judgment; cognitive decline; and slowing and slurred speech. PSP is often misdiagnosed as Parkinson disease due to similar symptoms. Onset is usually after age 60 but may occur earlier. Most cases of PSP appear to be sporadic, but familial cases have been reported. Some cases have been found to be caused by a mutation in the MAPT gene, and other genetic factors are being studied.
A rare late-onset neurodegenerative disease characterized by supranuclear gaze palsy, postural instability, progressive rigidity, and mild dementia. Epidemiology Prevalence is conservatively estimated at about 1/16,600. Clinical description PSP usually manifests during the sixth or seventh decade of life. Five clinical variants have been described with clinicopathological correlations: Classical PSP (Richardson's syndrome), and four atypical variants of PSP including PSP-Parkinsonism (PSP-P), PSP-Pure akinesia with gait freezing (PSP-PAGF), PSP-corticobasal syndrome (PSP-CBS), and PSP-progressive non fluent aphasia (PSP-PNFA) (see these terms). Richardson's syndrome is the most common clinical variant and manifests with a lurching gait, falls due to postural instability, cognitive impairment and slowing of vertical saccadic eye movements.
. ^ a b c d e f g h Harrison's principles of internal medicine (20 ed.). ... Creager, Mark A., Beckman, Joshua A., Loscalzo, Joseph. (2nd ed.). Philadelphia, PA: Elsevier/Saunders. 2013. ... (Fifty-eighth ed.). New York, N.Y. ISBN 9781260117431 . OCLC 1048597590. ^ a b c Peripheral Arterial Disease at Merck Manual of Diagnosis and Therapy Professional Edition. ... Fowkes, Gerry (ed.). "Angioplasty (versus non surgical management) for intermittent claudication".
Critical congenital heart disease (CCHD) is a term that refers to a group of serious heart defects that are present from birth. These abnormalities result from problems with the formation of one or more parts of the heart during the early stages of embryonic development. CCHD prevents the heart from pumping blood effectively or reduces the amount of oxygen in the blood. As a result, organs and tissues throughout the body do not receive enough oxygen, which can lead to organ damage and life-threatening complications. Individuals with CCHD usually require surgery soon after birth. Although babies with CCHD may appear healthy for the first few hours or days of life, signs and symptoms soon become apparent.
A number sign (#) is used with this entry because of evidence that hypoplastic left heart syndrome (HLHS2) is caused by heterozygous mutation in the NKX2-5 gene (600584) on chromosome 5q35.1. Description Hypoplastic left heart syndrome results from defective development of the aorta proximal to the entrance of the ductus arteriosus and hypoplasia of the left ventricle and mitral valve. As a result of the abnormal circulation, the ductus arteriosus and foramen ovale are patent and the right atrium, right ventricle, and pulmonary artery are enlarged (Brekke, 1953). For a discussion of genetic heterogeneity of hypoplastic left heart syndrome, see HLHS1 (241550). Molecular Genetics In 1 (1%) of 80 patients with hypoplastic left heart syndrome, McElhinney et al. (2003) identified heterozygosity for a missense mutation in the NKX2-5 gene (R25C; 600584.0004).
A number sign (#) is used with this entry because of evidence that hypoplastic left heart syndrome-1 (HLHS1) is caused by mutation in the GJA1 gene (121014) on chromosome 6q22. Description Hypoplastic left heart syndrome results from defective development of the aorta proximal to the entrance of the ductus arteriosus and hypoplasia of the left ventricle and mitral valve. As a result of the abnormal circulation, the ductus arteriosus and foramen ovale are patent and the right atrium, right ventricle, and pulmonary artery are enlarged (Brekke, 1953). Genetic Heterogeneity of Hypoplastic Left Heart Syndrome Hypoplastic left heart syndrome-2 (HLHS2; 614435) is caused by mutation in the NKX2-5 gene (600584) on chromosome 5q35.1. Somatic mutations in the HAND1 gene (602406) have been identified in tissue samples from patients with HLHS.
A rare, congenital, non-syndromic, heart malformation characterized by under development of the left-sided cardiac structures (including left ventricle, ascending aorta, aortic arch, and mitral and/or aortic valve) such that the left heart is unable to provide adequate systemic cardiac output. Epidemiology Hypoplastic left heart syndrome (HLHS) has been reported to occur in 1/3,500 to 12,500 live births. A male to female predominance ratio of 1.5:1 is observed. Clinical description Newborn infants with HLHS are generally born at full term. Initially appearing healthy, they are dependent upon the patent ductus arteriosus (PDA) for systemic blood flow. As the PDA closes, systemic perfusion decreases, resulting in hypoxemia, acidosis, and cardiogenic shock.
Hypoplastic left heart syndrome (HLHS) is a heart condition present from birth (congenital heart defect). In HLHS, the heart's left side (including the aorta, aortic valve, left ventricle and mitral valve) is underdeveloped. At birth, oxygen-rich blood bypasses the underdeveloped left side of the heart, going through openings between the left and right side that normally close a few days after birth (the patent ductus arteriosus and the patent foramen ovale). The right side of the heart then pumps blood to the lungs and the body. Therefore, there may be no symptoms for a few days. However, when these openings close, oxygen-rich blood cannot easily get to the rest of the body.
A rare cardiac disease characterized by acute occurrence of heart failure after an emotional or physical trigger however, recovery of the wall motion abnormalities are observed within months. Symptoms are similar to acute coronary syndrome (ACS). Epidemiology Takotsubo syndrome (TTS) is found in about 1-3% of all patients with symptoms of ACS; however, the prevalence is likely underestimated. Around 90% of TTS patients are women, typically postmenopausal but male and younger patients are diagnosed increasingly due to raised awareness of the syndrome. Clinical description In the acute phase, clinical presentation, electrocardiography (ECG) and cardiac biomarkers are similar to those of ACS. Typical symptoms are acute chest pain or dyspnea. Further symptoms can arise from complications of TTS, e.g. heart failure, cardiogenic shock, or cardiac arrest.