Alstrom syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

Alström syndrome is a rare genetic disorder caused by mutations in the gene ALMS1 which is located on the chromosome 2. It is among the rarest genetic disorders.

Alström syndrome was first described by Carl-Henry Alström in Sweden in 1959.

It is among the rarest genetic disorders in the world, as currently it has only 266 reported cases in medical literature and only 800 known cases in 54 countries.

It is possible to clinically detect Alström syndrome in infancy, but more frequently, it is detected much later, as doctors tend to detect symptoms as separate problems. Currently, Alström syndrome is only diagnosed clinically, since genetic testing is still rare and only available on a limited basis.

Electroretinogram is used for ophthalmologic evaluation. Screening esophagogastroduodenoscopy can be used to diagnose varices. Similarly upper GI endoscopy can aid in the diagnosis of gastroesophageal reflux.

The diagnosis of Alström syndrome relies primarily on clinical findings and/or family history. In some instances the diagnosis can be confirmed by molecular genetic testing. Sequence analysis of the coding region should be performed: tiered testing with sequencing of select exons first, followed by analysis of the entire gene. The frequency of deletions is unknown but deletion/duplication analysis may be clinically indicated in some instances^[1].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Alström syndrome was first described by Carl-Henry Alström in Sweden in 1959.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

The Jackson Laboratory in Bar Harbor, Maine, USA with the University of Southampton, UK isolated the single gene (ALMS1) responsible for Alstrőm Syndrome. The gene is recessive (it must be passed from both parents for the syndrome to manifest).

The key features are childhood obesity, blindness due to congenital cone-rod retinal dystrophy, and sensorineural hearing loss. Associated endocrinologic features include hyperinsulinemia, early-onset type 2 diabetes, and hypertriglyceridemia. Thus, AS shares several features with the common metabolic syndrome, namely obesity, hyperinsulinemia, and hypertriglyceridemia. Mutations in the ALMS1 gene have been found to be causative for AS with a total of 79 disease-causing mutations having been described.^[1]

• The cone-rod retinal dystrophy usually develops within the first few weeks after birth and the symptoms include nystagmus and extreme photodysphoria (light sensitivity). It is progressive and by the second decade of life leads to loss of perception of light (blindness).
• Most patients slowly develop bilateral sensorineural hearing loss.
• Dilated cardiomyopathy can develop at any age (infants or adolescents). It is seen in at least two-thirds of the patients and can lead to sudden cardiac failure.
• Birth weight is normal but infants develop truncal obesity by the end of first year.
• Insulin resistance develops in majority of children and is associated with acanthosis nigricans. By the end of third decade of life it eventually proceeds to type 2 diabetes mellitus with associated dyslipidemia.
• Other endocrine abnormalities usually seen in this disorder include hypothyroidism, hypogonadotropic hypogonadism in boys, and polycystic ovaries in girls.
• About 50% of individuals have delay in early developmental milestones; intelligence is normal.
• Liver involvement includes elevation of transaminases, steatosis, hepatosplenomegaly, and steatohepatitis. Portal hypertension and cirrhosis can lead to hepatic encephalopathy and life-threatening esophageal varices.
• Pulmonary dysfunction and severe renal disease may also develop. Pulmonary dysfunction can range from frequent bronchial infections to pulmonary fibrosis and pulmonary hypertension. Renal disease is progressive and the severity of glomerulosclerosis is highly variable. End-stage renal disease (ESRD) can occur as early as the late teens.

ALMS1 encodes a protein whose function is unknown. Mutations in this gene can lead to production of a dysfunctional protein that might be responsible for the signs and symptoms of Alstrom disease. Alström syndrome (AS) is a rare autosomal recessive disease characterized by multi-organ dysfunction.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

Alstrom syndrome is a ciliopathy. It should be differentiated from the following disorders:

Bardet-Biedl syndrome shares some features of Alström syndrome. The major clinical features of BBS are:

• Rod-cone dystrophy
• Postaxial polydactyly
• Central obesity
• Cognitive impairment
• Hypogonadism and
• Renal dysfunction

A major difference between Alström syndrome and BBS is the timing of the onset of visual problems:

• In Alström syndrome, visual problems are usually apparent in the first two years of life; in BBS, the average age of onset of visual problems is 8.5 years.
• Polydactyly, which is common in BBS, has not been described in Alström syndrome.
• Cognitive impairment is well described in BBS, while in most persons with Alström syndrome intelligence is normal, but delays in early milestones have been reported.
• Other differences include the relative infrequency of hearing problems (~5%) and diabetes mellitus (5%-10%) in BBS compared with Alström syndrome. Mutations in at least 14 different genes are causative. Inheritance is autosomal recessive.

Other ciliopathies that should be differentiated from Alstrom syndrome include:

• Primary ciliary dyskinesia
• Polycystic kidney disease
• Polycystic liver disease
• Nephronophthisis
• Meckel-Gruber syndrome
• Biemond II syndrome
• Wolfram syndrome
• Cohen syndrome
• Sporadic infantile DCM
• Mitochondrial disorders
• Achromatopsia
• Leber congenital amaurosis
• Some forms of retinal degeneration^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Alstrom syndrome is among the rarest genetic disorders in the world, as currently it has only 266 reported cases in medical literature and only 800 known cases in 54 countries.

Template:WikiDoc Sources CME Category::Cardiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

• Fasting blood glucose levels are evaluated every two to three months. Closer follow-up is needed if fasting or postprandial blood glucose concentrations are elevated.
• Urinalysis and plasma concentrations of electrolytes, uric acid, BUN, and creatinine should be estimated twice-yearly.
• Annual assessment of vision and hearing; weight, height, and body mass index; heart (including echocardiography); plasma insulin concentration; lipid profile; plasma ALT, AST, and GGT concentrations; pulmonary function; thyroid function.
• Renal and bladder ultrasound examinations should be conducted if symptomatic and/or if urinalysis is abnormal, every one to two years.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

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A wide range of clinical variability is observed among individuals with Alström syndrome, including among siblings. The first clinical presentation of Alström syndrome is usually nystagmus caused by cone-rod dystrophy and resulting in childhood blindness. Disease characteristics that are later in onset include truncal obesity that manifests during the first year of life, progressive sensorineural hearing loss, infantile-onset dilated cardiomyopathy or later-onset restrictive cardiomyopathy, insulin-resistant type 2 diabetes mellitus, and hepatic, pulmonary, and renal dysfunction.

• Vision problems are progressive and ultimately result in blindness. Rod function is preserved initially but deteriorates as the individual ages, with visual acuity of 6/60 or less by age ten years, increasing constriction of visual fields, and no light perception by age 20 years. In some rare cases, some vision (e.g., the ability to read large print) is retained into the third decade.
• Hyperphagia and excessive weight gain (some studies show weight gain greater than expected for intake) begin during their first year, resulting in childhood truncal obesity. In some individuals body weight tends to normalize, decreasing into the high-normal to normal range after adolescence.
• Hearing loss may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade. A high incidence of glue ear (long-standing sticky fluid in the middle ear) can lead to an additional conductive hearing loss.
• More than 60% of individuals with Alström syndrome develop congestive heart failure as a result of cardiomyopathy at some stage of their lives. Onset, progression, and clinical outcome of the cardiomyopathy vary, even within families. More than 40% of affected infants have a transient but severe dilated cardiomyopathy with onset between age three weeks and four months. Most of these children survive and make an apparently full recovery in infancy. At a later age about 10%-15% of this group have spontaneous recurrence of a progressive restrictive cardiomyopathy. The proportion of those with Alström syndrome who develop infantile-onset cardiomyopathy may be underestimated because some infants who succumb may have undiagnosed Alström syndrome. About 20% of individuals with Alström syndrome have later-onset progressive restrictive cardiomyopathy identified between the teens to late 30s. Cardiac magnetic resonance imaging suggests that myocardial fibrosis may be present in clinically affected and asymptomatic individuals.
• In a small study of 12 unrelated individuals with Alström syndrome, obesity (BMI and waist circumference) decreased with age, whereas insulin resistance increased with age.
• Growth rates for young children are normal, but accelerated skeletal maturity (2-3 years advanced bone age) and low-serum growth hormone concentrations result in adult stature that is typically less than the 25th centile. In about 98% of individuals over age 16 years height is below the fifth centile.
• Renal disease is common, slowly progressive, and highly variable, and may be unrelated to diabetes; it manifests as tubulo-interstitial disease resulting from interstitial fibrosis. Initial signs of mildly elevated serum concentrations of creatinine and blood urea nitrogen (BUN) may be followed by polyuria and polydipsia resulting from a concentrating defect. Onset can be in mid-childhood through adulthood. End-stage renal disease (ESRD) can occur as early as the mid- to late teens.
• Progression to cirrhosis and hepatic failure can occur in the second to third decades, and the complications of portal hypertension, ascites, splenomegaly, hepatic encephalopathy, and esophageal varices are also seen.
• Recurrent chest infections are common at all ages. Most frequently there is a combination of restrictive lung disease due to kyphoscoliosis and sometimes pulmonary fibrosis, which has been confirmed in post mortem tissue and may be detected in life with high-resolution chest CT scan. This may progress (with the added effects of cardiomyopathy) to pulmonary hypertension. The resulting susceptibility to severe hypoxia postoperatively or during episodes of pneumonia has been reported.

• Blindness
• Hearing loss
• Congestive heart failure
• Cirrhosis
• Pancreatitis
• ESRD
• Hypothyroidism
• Pulmonary fibrosis
• Portal hypertension
• Type 2 diabetes mellitus
• Stunted growth

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