Yao syndrome (formerly called NOD2 -associated autoinflammatory disease) is a disorder involving episodes of fever and abnormal inflammation affecting many parts of the body, particularly the skin, joints, and gastrointestinal system. Inflammation is a normal immune system response to injury and foreign invaders (such as bacteria). In people with Yao syndrome, part of the immune system called the innate immune response is turned on (activated) abnormally, which causes fevers and inflammation-related damage to tissues and organs. Based on this process, Yao syndrome is classified as an autoinflammatory disease. Autoinflammatory diseases are distinct from autoimmune diseases; these two groups of diseases involve abnormalities in different parts of the immune system.

Clinical Features Yao et al. (2011) described 7 unrelated patients with apparent autoinflammatory disease with multisystem involvement. Mean age at disease onset was 40.7 years, and the patients characteristically presented with periodic fever, dermatitis, and inflammatory polyarthritis. ... Yao et al. (2013) studied 22 patients with autoinflammatory disease, including the 7 previously reported by Yao et al. (2011). Mean age at diagnosis was 40 years, with a range from age 17 to 72 years, and mean disease duration of 4.7 years.

In a 2-stage genomewide scan of 71 multicase leprosy families (365 individuals) in Brazil, Miller et al. (2004) found suggestive evidence for linkage to chromosomes 6p21.32, 17q22, and 20p13.

A number sign (#) is used with this entry because this form of susceptibility to leprosy (LPRS5) is associated with a polymorphism in the TLR1 gene (601194). A polymorphism in the TLR1 gene is also associated with protection against leprosy. See 609888 for a discussion of leprosy susceptibility in general and information on genetic heterogeneity. Mapping LPRS5 is associated with a polymorphism in the TLR1 gene, which Taguchi et al. (1996) mapped to chromosome 4p14. Molecular Genetics Schuring et al. (2009) studied association of an asn248-to-ser (N248S; 601194.0002) SNP in the TLR1 gene and leprosy in a Bangladeshi population consisting of 842 patients and 543 controls.

See 609888 for a discussion of leprosy susceptibility in general and information on genetic heterogeneity. Mapping In a study in a Vietnamese population, Mira et al. (2003) found significant evidence for a susceptibility gene for leprosy on chromosome region 6q25; maximum likelihood binomial (MLB) lod score was 4.31. They confirmed this by family-based association analysis in an independent panel of 208 Vietnamese leprosy simplex families (i.e., families with 2 unaffected parents and 1 affected child). Mira et al. (2003) confirmed the linkage of paucibacillary leprosy to 10p13 (LPRS1; 609888), as reported by Siddiqui et al. (2001). Their evidence suggested that the 6q25 locus is involved in leprosy of both the paucibacillary and multibacillary types.

A number sign (#) is used with this entry because this form of susceptibility to leprosy (LPRS3) is associated with a polymorphism in the TLR2 gene (603028) on chromosome 4q32. See 609888 for a discussion of leprosy susceptibility in general and information on genetic heterogeneity. Mapping LPRS3 is associated with a polymorphism in the TLR2 gene, which Rock et al. (1998) mapped to chromosome 4q32. Molecular Genetics Kang and Chae (2001) identified an arg677-to-trp polymorphism (R677W; 603028.0001) in the intracellular domain of TLR2 in 10 (22%) of 45 Korean lepromatous leprosy patients, but not in any of 41 Korean tuberculoid patients or 45 Korean controls. They concluded that the R677W polymorphism in TLR2 has a role in susceptibility to lepromatous leprosy.

See 609888 for a discussion of leprosy susceptibility in general and information on genetic heterogeneity. Mapping Zhang et al. (2009) performed a genomewide association study to identify leprosy susceptibility loci in 706 patients and 1,225 controls, all of whom were self-identified Han Chinese from eastern China. Diagnosis was made on the basis of the consensus of at least 2 dermatologists. Patients and controls reported an absence of M. tuberculosis and other chronic infections. Controls lacked a history of leprosy in themselves and their families, as well as autoimmune and systemic disorders.

A chronic infectious disease affecting primarily the skin and peripheral nervous system. Epidemiology Worldwide annual incidence is estimated at 250,000 cases, with a large majority in India and Brazil. Clinical description A wide clinical spectrum has been described from a polar tuberculoid (localized) form (TT) to a polar lepromatous (disseminated) one (LL). Borderline forms exist: borderline tuberculoid, borderline borderline and borderline lepromatous (BT, BB, BL). Tuberculoid leprosy (TLep) or paucibacillary form includes TT and BT and lepromatous leprosy (LLep) or multibacillary form includes LL, BL and BB.

Leprosy Other names Hansen's disease (HD) [1] Rash on the chest and abdomen due to leprosy Pronunciation / ˈ l ɛ p r ə s i / [2] Specialty Infectious disease Symptoms Decreased ability to feel pain [3] Causes Mycobacterium leprae or Mycobacterium lepromatosis [4] [5] Risk factors Close contact with a case of leprosy, living in poverty [3] [6] Treatment Multidrug therapy [4] Medication Rifampicin , dapsone , clofazimine [3] Frequency 209,000 (2018) [7] Leprosy , also known as Hansen's disease ( HD ), is a long-term infection by the bacteria Mycobacterium leprae or Mycobacterium lepromatosis . [4] [8] Infection can lead to damage of the nerves , respiratory tract , skin, and eyes. [4] This nerve damage may result in a lack of ability to feel pain, which can lead to the loss of parts of a person's extremities from repeated injuries or infection due to unnoticed wounds. [3] An infected person may also experience muscle weakness and poor eyesight. [3] Leprosy symptoms may begin within one year, but for some people symptoms may take 20 years or more to occur. [4] Leprosy is spread between people, although extensive contact is necessary. [3] [9] About 95% of people who contract M. leprae do not develop the disease. [10] Spread is thought to occur through a cough or contact with fluid from the nose of a person infected by leprosy. [9] [10] Genetic factors and immune function play a role in how easily a person catches the disease. [10] [11] Leprosy does not spread during pregnancy to the unborn child, or through sexual contact. [9] Leprosy occurs more commonly among people living in poverty. [3] There are two main types of the disease – paucibacillary and multibacillary, which differ in the number of bacteria present. [3] A person with paucibacillary disease has five or fewer poorly pigmented numb skin patches while a person with multibacillary disease has more than five skin patches. [3] The diagnosis is confirmed by finding acid-fast bacilli in a biopsy of the skin. [3] Leprosy is curable with multidrug therapy. [4] Treatment of paucibacillary leprosy is with the medications dapsone , rifampicin , and clofazimine for six months. [10] Treatment for multibacillary leprosy uses the same medications for 12 months. [10] A number of other antibiotics may also be used. [3] These treatments are provided free of charge by the World Health Organization . [4] People with leprosy can live with their families and go to school and work. [12] In 2018, there were 209,000 leprosy cases globally, down from 5.2 million in the 1980s. [7] [13] [14] The number of new cases in 2016 was 216,000. [4] Most new cases occur in 14 countries, with India accounting for more than half. [3] [4] In the 20 years from 1994 to 2014, 16 million people worldwide were cured of leprosy. [4] About 200 cases per year are reported in the United States. [15] Leprosy has affected humanity for thousands of years. [3] The disease takes its name from the Greek word λέπρᾱ ( léprā ), from λεπῐ́ς ( lepís ; "scale"), while the term "Hansen's disease" is named after the Norwegian physician Gerhard Armauer Hansen . [3] Leprosy has historically been associated with social stigma , which continues to be a barrier to self-reporting and early treatment. [4] Separating people affected by leprosy by placing them in leper colonies still occurs in some areas of India, [16] China, [17] Africa, [18] and Thailand. [19] Most colonies have closed, as leprosy is not very contagious. [18] Some consider the word "leper" offensive, preferring the phrase "person affected with leprosy". [20] Leprosy is classified as a neglected tropical disease . [21] World Leprosy Day was started in 1954 to draw awareness to those affected by leprosy. [22] Contents 1 Signs and symptoms 2 Cause 2.1 M. leprae and M. lepromatosis 2.2 Risk factors 2.3 Transmission 2.4 Genetics 3 Mechanism 4 Diagnosis 4.1 Classification 5 Prevention 6 Treatment 6.1 Anti-leprosy medication 6.2 Skin changes 7 Epidemiology 7.1 Disease burden 8 History 9 Society and culture 9.1 India 9.2 Treatment cost 9.3 Historical texts 9.4 Middle Ages 9.5 19th century 9.5.1 Norway 9.5.2 Colonialism and imperialism 9.6 Stigma 9.7 Programs and treatment 10 Notable cases 11 Coverage in the media 12 Other animals 13 See also 14 References 15 Further reading 16 External links Signs and symptoms [ edit ] Common symptoms present in the different types of leprosy include a runny nose; dry scalp; eye problems; skin lesions; muscle weakness; reddish skin; smooth, shiny, diffuse thickening of facial skin, ear, and hand; loss of sensation in fingers and toes; thickening of peripheral nerves; a flat nose due to destruction of nasal cartilage; and changes in phonation and other aspects of speech production. [23] [24] In addition, atrophy of the testes and impotence may occur. [25] Leprosy can affect people in different ways. [10] The average incubation period is 5 years. [4] People may begin to notice symptoms within the first year or up to 20 years after infection. [4] The first noticeable sign of leprosy is often the development of pale or pink coloured patches of skin that may be insensitive to temperature or pain. [26] Patches of discolored skin are sometimes accompanied or preceded by nerve problems including numbness or tenderness in the hands or feet. [26] [27] Secondary infections (additional bacterial or viral infections) can result in tissue loss, causing fingers and toes to become shortened and deformed, as cartilage is absorbed into the body. [28] [29] A person's immune response differs depending on the form of leprosy. [30] Approximately 30% of people affected with leprosy experience nerve damage. [31] The nerve damage sustained is reversible when treated early, but becomes permanent when appropriate treatment is delayed by several months. ... While this text defines the leper as impure , it did not explicitly make a moral judgement on those with leprosy. [126] Some Early Christians believed that those affected by leprosy were being punished by God for sinful behavior. [ citation needed ] Moral associations have persisted throughout history. [ citation needed ] Pope Gregory the Great (540–604) and Isidor of Seville (560–636) considered people with the disease to be heretics. [127] Middle Ages [ edit ] This article is missing information about perspective of medieval leprosy in Orthodox lands (e.g. ... Further details may exist on the talk page . ( August 2020 ) Medieval leper bell It is believed that a rise in leprosy in Western Europe occurred in the Middle Ages based on the increased number of hospitals created to treat people with leprosy in the 12th and 13th centuries. [128] [129] [130] France alone had nearly 2,000 leprosariums during this period. [131] The social perception of leprosy in medieval communities was generally one of fear, and people infected with the disease were thought to be unclean, untrustworthy, and morally corrupt. [127] Segregation from mainstream society was common, and people with leprosy were often required to wear clothing that identified them as such or carry a bell announcing their presence. [131] The third Lateran Council of 1179 and a 1346 edict by King Edward expelled lepers from city limits. ... Science 308: 1040–1042. ^ a b Han, Xiang Y.; Silva, Francisco J.; Baker, Stephen (13 February 2014). "On the Age of Leprosy" . PLOS Neglected Tropical Diseases . 8 (2): e2544. doi : 10.1371/journal.pntd.0002544 .

Hansen's disease (also known as leprosy) is a rare bacterial infection that affects the skin, nerves and mucous membranes . After exposure, it may take anywhere from 2 to 10 years to develop features of the condition. Once present, common signs and symptoms include skin lesions ; muscle weakness or paralysis; eye problems that may lead to blindness; nosebleeds; severe pain; and/or numbness in the hands, feet, arms and legs. Hansen's disease is caused by the bacterium Mycobacterium leprae; however, the way in which the bacterium is transmitted (spread) is poorly understood. It appears that only about 5% of people are susceptible to the condition.

The proband presented at 18 months of age with impaired vision and was found to have microspherophakia with bilateral lens dislocation, megalocornea, flat irides, and iridodonesis. ... He underwent bilateral lensectomy at 2 years of age; 4 to 5 years later he had bilateral retinal detachment, and ocular hypertension developed. ... She had complete posterior lens dislocation at 6 years of age, and ocular hypertension was noted at 8 years of age. ... At 5 years of age, she had intermittent anterior dislocation of the left lens, causing acute glaucoma crises, and she underwent emergent extraction of the lens; left retinal detachment developed a few weeks later. ... Reexamination of the proband at 14 years of age revealed an increased arm span of 204 cm with a height of 184 cm, and a decreased upper-to-lower body ratio.

Glaucoma secondary to spherophakia/ectopia lentis and megalocornea is a rare, genetic, non-syndromic developmental defect of the eye disorder characterized by congenital megalocornea associated with spherophakia and/or ectopia lentis leading to pupillary block and secondary glaucoma. Additional features may include flat irides, iridodonesis, axial myopia, very deep anterior chambers, miotic, oval pupils without well-defined borders, ocular pain and irritability manifesting as conjunctival injection, corneal edema and central scarring, as well as a high arched palate.

TEMPI syndrome is a rare multi-systemic disease characterized by the presence of Telangiectasias, Erythrocytosis with elevated erythropoietin levels, Monoclonal gammopathy, Perinephric-fluid collections, and Intrapulmonary shunting. Epidemiology Less than 10 cases have been described in the literature. Clinical description TEMPI syndrome manifests in mid-adulthood with the development of telangiectasias mostly on the face, trunk and arms, as well as with erythrocytosis which may cause a red facies and occasionally, headaches. The increased serum erythropoietin levels precede the intrapulmonary shunting. The intrapulmonary shunts cause hypoxia which slowly progresses until the person needs continuous supplemental oxygen.

TEMPI syndrome is a newly discovered, multisystem condition named for 5 characteristics that affected individuals have: T elangiectasias , E rythrocytosis with elevated erythropoietin level , M onoclonal gammopathy , P erinephric-fluid collections (fluid around the kidney), and I ntrapulmonary shunting (when a region of the lungs is supplied with blood but with little or no ventilation). Signs and symptoms of TEMPI syndrome have appeared in mid-adulthood in all known affected individuals. The telangiectasias develop mostly on the face, trunk and arms. The intrapulmonary shunt causes hypoxia (not enough oxygen supply), which slowly progresses until the person needs continuous supplemental oxygen to support their breathing. Blood clots and bleeding in the brain have also been reported in some affected individuals. The cause of TEMPI syndrome is currently unknown. Treatment has reportedly been completely or partially successful with the medication bortezomib .

Garrod's pads (also known as violinist's pads [1] ) are a cutaneous condition characterized by calluses on the dorsal aspect of the interphalangeal joints , [2] i.e. the back side of the finger joints. They are often seen in violin , viola , and cello players, along with fiddler's neck and other dermatologic conditions peculiar to string musicians. [2] Although Garrod's pads are conventionally described as appearing on the proximal interphalangeal joint, distal interphalangeal joint involvement has also been described. [2] Garrod's pads are named after Archibald Garrod who first documented them in 1904 in association with Dupuytren's contracture . [3] H.A. Bird described them as an incidental finding in a professional violinist and proposed that they arise in such cases due to repeated extreme tension of the extensor tendons over the interphalangeal joints. [4] Bird noted that violin players use the left hand for a markedly different task than the right hand, with the extensor tendons in the left hand subjected to considerable tension, and that Garrod's pads only arise on the left hand in such cases. This unilateral finding differentiates the occupational hazard of Garrod's pads from more significant disorders. Among violinists and violists, Garrod's pads apparently arise as a protective mechanism for the skin and subcutaneous tissues above the tendons; Bird notes that they do not protect against external trauma unlike most calluses. [4] Patients with Dupuytren's contracture are four times more likely to have coexisting Garrod's pads. [5] [6] See also [ edit ] Knuckle pads Harpist's finger Fiddler's neck Cellist's chest Cello scrotum Paget-Schroetter syndrome List of cutaneous conditions List of eponymously named medical signs References [ edit ] ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007).

A number sign (#) is used with this entry because knuckle pads are associated with certain genetic disorders such as epidermolytis palmoplantar keratoderma (144200) or Dupuytren contractures (126900), both of which are autosomal dominant. Knuckle pads are sometimes associated with Dupuytren contractures and it is not completely certain that a different gene is involved. Camptodactyly (114200) also has an uncertain relationship. Skoog (1948) defined knuckle pads as 'subcutaneous nodules on the dorsal aspect of the proximal interphalangeal joints.' Lu et al. (2003) reported association of knuckle pads with epidermolytic palmoplantar keratoderma in a Chinese family and identified a novel leu160-to-phe mutation in the keratin-9 gene (L160F; 607606.0012) as the presumed cause. They presented evidence that both the hyperkeratosis and the knuckle pads were friction-related.

People with multiple myeloma typically develop the disorder around age 65. Over time, affected individuals can develop life-threatening complications, but the rate at which this happens varies widely.

A plasma cell disorder characterized by the aggregation and deposition of insoluble amyloid fibrils derived from misfolding of monoclonal immunoglobulin light chains usually produced by a plasma cell tumor. It usually presents as primary systemic amyloidosis (PSA) with multiple organ involvement and less frequently as primary localized amyloidosis (PLA) restricted to a single organ.

AL amyloidosisis the most common form of amyloidosis, a group of disorders in which an abnormal protein called amyloid builds up in tissues and organs. The signs and symptoms of AL amyloidosis vary among patients because the build up may occur in the tongue, intestines, muscles, joints, nerves, skin, ligaments, heart, liver, spleen, or kidneys. To diagnose AL amyloidosis, healthcare professionals use blood or urine tests to identify signs of amyloid protein and a biopsy to confirm the diagnosis. Treatment may include chemotherapy directed at the abnormal plasma cells, stem cell transplantation , or other treatments based on which symptoms have developed.

Primary systemic amyloidosis (PSA) is a form of AL amyloidosis (see this term) caused by the aggregation and deposition of insoluble amyloid fibrils derived from misfolded monoclonal immunoglobulin light chains usually produced by a plasma cell tumor (see this term) and characterized by multiple organ involvement.

Eosinophilic pustular folliculitis (EPF) affects the skin causing itchy, red or skin-colored bumps and pustules (bumps containing pus). The papules mostly appear on the face, scalp, neck and trunk and may last for weeks or months. EPF affects males more than females. There are several forms of EPF. Classic eosinophilic pustular folliculitis mainly occurs in Japan. Immunosuppression-associated EPF is mainly associated with HIV infection, but has also been associated with certain cancers and medications.[16046] The infantile form of EPF is seen in infants from birth or within the first year of life. The underlying cause of EFP is unknown. All of these forms have similar skin findings.

For a general phenotypic description and a discussion of genetic heterogeneity of Alzheimer disease, see 104300. Mapping Liu et al. (2007) conducted a genome screen of 103 patients with late-onset AD who were ascertained as part of the Genetic Research in Isolated Populations (GRIP) program that was conducted in an isolated population from the southwestern area of the Netherlands. Genealogic information resulted in an extremely large and complex pedigree of 4,645 members. The pedigree was split into 35 subpedigrees to reduce the computational burden of linkage analysis. The strongest evidence for linkage, hlod = 5.20 at marker D1S498, was obtained at chromosome 1q21 (AD13).

Early-onset, autosomal dominant Alzheimer disease is a form of Alzheimer disease (AD) that develops before the age of 65. It is diagnosed in families that have more than one member with AD (usually multiple persons in more than one generation) in which the age of onset is consistently before age 60 and often between the ages of 30 and 60 years. ... There are three subtypes of early-onset familial AD which are each associated with changes (mutations) in unique genes: (1) Alzheimer disease, type 1 is caused by mutations in the APP gene (2) Alzheimer disease, type 3 is caused by mutations in the PSEN1 gene (3) Alzheimer disease, type 4 is caused by mutations in the PSEN2 gene.

Scott et al. (2003) reexamined 437 white AD families included in the original report by Pericak-Vance et al. (2000) by considering age of onset as a covariate. Ordered-subsets analysis included continuous covariates in linkage analysis by rank ordering families by a covariate and summing lod scores. The lod score in the 9p22 region previously linked to AD increased to 4.6 at D9S741 in 334 families with minimum age at onset between 60 and 75 years. The analysis also identified linkage to 2q34, with a peak nonparametric multipoint lod score of 3.2 at D2S2944 in 31 families with a minimum age at onset between 50 and 60 years. ... Farrer et al. (2003) observed an unusually high prevalence of dementia of the Alzheimer type in Wadi Ara, an inbred Arab community in northern Israel comprising approximately 850 persons over the age of 60 years. A 10-cM genomic scan revealed significant allelic association with AD (p less than 0.05) at locations on chromosomes 2, 9, 10, and 12.

These individuals were on average 11.3 years younger than the onset age of their parents. All were APOE4-(107741) negative. ... The findings indicated that SORCS1 can influence APP processing, and Reitz et al. (2011) suggested that variation in the SORCS1 gene may be associated with risk of LOAD. ... The CT and TT genotypes of rs2227564 were associated with LOAD (p = 0.05) and with age-dependent elevation of plasma A-beta-42 in 24 extended LOAD families (p = 0.0006). In Plau-knockout mice, plasma A-beta-42 and A-beta-40 levels, but not levels in brain, were significantly elevated in an age-dependent manner. Grupe et al. (2006) reported no association between AD and the PLAU gene. ... The findings indicated a role for calcium signaling in APP (104760) processing and suggested that variations in the CALHM1 gene may influence susceptibility to late-onset AD.

Their results extended and provided modest evidence of linkage to loci on 12p. Linkage varied by age at onset of AD and by the presence or absence of the APOE epsilon-4 allele. Lod scores were lower when the E4 allele (107741.0016) was present; the lod score was reduced in families with onset after 65 years of age. Lambert et al. (2000) reported an association between a noncoding polymorphism (G-A) in the 3-prime untranslated region of transcription factor CP2 (TCFP2; 189889) and sporadic AD in French and British populations and a similar trend in a North American population. ... No significant effects were found when the data were adjusted for age, sex, or the presence of the apoE E4 allele. Farrer et al. (2003) observed an unusually high prevalence of dementia of the Alzheimer type in Wadi Ara, an inbred Arab community in northern Israel in which approximately 850 persons were over the age of 60 years. A 10-cM genomic scan revealed significant allelic association with AD (p less than 0.05) at locations on chromosomes 2, 9, 10, and 12.

Bateman et al. (2012) used the participant's age at baseline assessment and the parent's age at the onset of symptoms of AD to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). ... The mean age of onset of dementia was 43 years. ... In the 5 index cases with the combination of early-onset Alzheimer disease and CAA, they found evidence for a duplication of the APP locus (104760.0020). In the corresponding families, the APP locus duplication was present in affected subjects but not in healthy subjects over the age of 60 years. ... Revesz et al. (2003) reviewed the pathology and genetics of APP-related CAA and discussed the different neuropathologic consequences of different APP mutations. ... Di Fede et al. (2009) identified a homozygous mutation in the APP gene (A673V; 104760.0022) in a patient with early-onset progressive AD beginning at age 36 years.

INHERITANCE - Autosomal dominant NEUROLOGIC Central Nervous System - Alzheimer disease - Seizures - Cerebral cortex with spongiform changes - Neurofibrillary tangles - Beta-amyloid-positive senile plaques - Prion protein-positive senile plaques MISCELLANEOUS - Age of onset 43-64 years ▲ Close

Mapping In a linkage study of 272 affected sib pairs (ASPs) with AD who were 60 years of age or older at onset, Blacker et al. (1997) found strong evidence of linkage on chromosomes 20 (lod score = 4.09) and 21 (lod score = 5.9). ... Within this candidate region, 1 gene of particular interest was that encoding cystatin-3 (CST3; 604312), because it is known to be an amyloidogenic protein and is codeposited with the amyloid-beta precursor protein (APP; 104760) in amyloid plaques in the brain of AD patients. Using a covariate-based linkage method, Olson et al. (2001) showed that the APP region on chromosome 21q21 is strongly linked to AD-affected sib pairs of the oldest current age (i.e., age either at last exam or at death) who lacked E4 alleles at the apolipoprotein E (APOE; 107741) locus. In further use of a covariate-based linkage method to reanalyze genome scan data, Olson et al. (2002) determined that a region on chromosome 20p showed the same pattern. A model that included current age and the number of E2 alleles at the APOE locus as covariates gave a lod score of 4.1. ... Two-locus analysis provided evidence of strong epistasis between 20p and the APP region, limited to the oldest age group and to those lacking E4 alleles at the APOE locus.

EOAD presents the same phenotype as sporadic Alzheimer disease (AD) but has an early age of onset, usually before 60 years old. ... Etiology EOAD is the consequence of either PSEN1 mutations (69%), APP mutations (13%), or APP duplication (7,5%), and exceptionally of PSEN2 mutations (2%). ... Lumbar puncture for measurement of cerebrospinal fluid tau and amyloid may be useful (tau and phosphorylated tau are often elevated and amyloid is usually low). Age of onset before 60 years suggests an EOAD and needs a pedigree.

Other than the relatively early age at onset, AD in the Volga group was clinically and pathologically indistinguishable from typical AD. Bird et al. (1996) reported that the mean age at onset in the Volga Germans is 54.9 years, mean age at death is 65.9 years, and mean disease duration is 11.3 years. These findings contrasted with families with chromosome 14-linked AD (AD3; 607822), in which the mean age at onset is 44.8 years, mean age at death is 52.6 years, and mean disease duration is 7.6 years. ... Finckh et al. (2000) noted that there may be variable age at onset, reduced penetrance, or other genetic disease modifiers. ... There was no clinical correlation between age at onset or disease severity with Lewy body pathology in either group.

When Alzheimer disease begins before 60 or 65 years of age (early-onset AD) about 60% of the cases are familial (also known as Early-onset familial AD). ... There are three subtypes of early-onset familial AD which are each associated with changes (mutations) in unique genes: (1) Alzheimer disease, type 1 is caused by mutations in the APP gene (2) Alzheimer disease, type 3 is caused by mutations in the PSEN1 gene (3) Alzheimer disease, type 4 is caused by mutations in the PSEN2 gene.

For a general phenotypic description and a discussion of genetic heterogeneity of Alzheimer disease, see 104300. Mapping Liu et al. (2007) conducted a genome screen of 103 patients with late-onset AD who were ascertained as part of the Genetic Research in Isolated Populations (GRIP) program that was conducted in an isolated population from the southwestern area of the Netherlands. Genealogic information resulted in an extremely large and complex pedigree of 4,645 members. The pedigree was split into 35 subpedigrees to reduce the computational burden of linkage analysis. They found significant evidence of linkage of AD to 3q22-q24 (AD15), in a region of 18 cM from D3S3514 to D3S3626 that reached a maximum hlod of 4.44 at marker D3S1579.

For a general phenotypic description and a discussion of genetic heterogeneity of Alzheimer disease, see 104300. Mapping In a genome screen of individuals from an isolated population from the southwestern area of the Netherlands, ascertained as part of the Genetic Research in Isolated Populations (GRIP) program, Liu et al. (2007) found the strongest evidence of linkage for chromosome 1q21 (AD13; 611152). Approximately 30 cM upstream of this locus, at 1q25, another peak (AD14) was found (hlod = 4.0 at marker D1S218). Liu et al. (2007) noted that these 2 loci were in a linkage region spanning 1q21-q31 identified by Zubenko et al. (1998), Hiltunen et al. (2001), Myers et al. (2002), and Blacker et al. (2003). Haplotype analysis showed that the 2 linkage peaks on chromosome 1q21 and 1q25 are explained by different haplotypes, of 15 cM and 21 cM, respectively, segregating in different families.

Mapping Giedraitis et al. (2006) conducted a genome scan with 369 microsatellite markers in 12 extended families collected in Sweden. Age at disease onset ranged from 53 to 78 years, but in 10 of the families there was at least 1 member with age at onset of less than 65 years.

Clinical Features Campion et al. (1995) studied a large pedigree that included 34 subjects with early-onset progressive dementia with mean age at onset at 46 plus or minus 3.5 years and mean age at death at 52.6. ... He had rapid progression with global impairment of all cognitive functions and became bedridden, anarthric, and incontinent by age 33. He died of bronchopneumonia at age 35. ... The proband developed memory problems at age 28 years. At age 31, he had mild bilateral limb apraxia, dystonia, mild dementia, and hypometabolism of the temporoparietal association cortex on PET scan. ... Evidence of linkage to D14S52 was found for a subgroup of families of intermediate age of onset, namely, older than 60 but less than 70 years of age. ... The brothers had onset of progressive dementia and ataxia between ages 29 and 32 years; 2 died at age 32 and the other died at age 36.

INHERITANCE - Autosomal dominant NEUROLOGIC Central Nervous System - Memory impairment - Dementia - Praxis - Speech impairment - Neuroimaging shows cortical atrophy Behavioral Psychiatric Manifestations - Personality changes MISCELLANEOUS - Mean age at onset 66.8 years (range 47-77) ▲ Close

Zubenko et al. (2001) described a prospective, longitudinal, double-blind assessment of the age-specific risk of AD encountered by 325 asymptomatic first-degree relatives of AD probands who carried the D10S1423 234-bp allele, the APOE E4 allele (107741), or both, after 11.5 years of systematic follow-up.