Alstrom Syndrome

A number sign (#) is used with this entry because of evidence that Alstrom syndrome (ALMS) is caused by homozygous or compound heterozygous mutation in the ALMS1 gene (606844) on chromosome 2p13.

Description

Alstrom syndrome is an autosomal recessive disorder characterized by progressive cone-rod dystrophy leading to blindness, sensorineural hearing loss, childhood obesity associated with hyperinsulinemia, and type 2 diabetes mellitus. Dilated cardiomyopathy occurs in approximately 70% of patients during infancy or adolescence. Renal failure, pulmonary, hepatic, and urologic dysfunction are often observed, and systemic fibrosis develops with age (summary by Collin et al., 2002; Marshall et al., 2007).

Clinical Features

Although this disorder bears many similarities (retinitis pigmentosa, deafness, obesity, and diabetes mellitus) to the Bardet-Biedl syndrome (209900), there is no mental defect, polydactyly, or hypogonadism (Alstrom et al., 1959). The retinal lesion causes nystagmus and early loss of central vision in contrast to loss of peripheral vision first, as in other pigmentary retinopathies.

Weinstein et al. (1969) described the condition of 2 brothers with a disorder that they suggested 'resembles that described by Alstrom and his co-workers.' In spite of the presence of small testes and elevated urinary gonadotropin levels, secondary sexual characteristics were normal. Associated findings were blindness, deafness, obesity, and several metabolic abnormalities including hyperuricemia and elevated serum triglyceride and pre-beta-lipoprotein. Warren et al. (1987) gave follow-up on the brothers reported by Weinstein et al. (1969). Both developed manifestations of dilated cardiomyopathy at about the same age, 36 and 37 years. Myocardial fibrosis was demonstrated at autopsy and on myocardial biopsy; not enough in the way of coronary artery disease was found to explain the heart disease.

Charles et al. (1990) described Alstrom syndrome in the offspring of a couple related as first cousins once removed.

Connolly et al. (1991) described an 11-year-old girl from an isolated Mennonite community in British Columbia who, in addition to having pigmentary retinopathy, sensorineural deafness, obesity, type II diabetes mellitus, hyperlipidemia, and acanthosis nigricans, developed chronic active hepatitis at the age of 8 years. This disorder is unusually frequent among French Acadians, both those living in Yarmouth County, Nova Scotia, and in Louisiana, where the syndrome may have been confused with Bardet-Biedl syndrome. See later for a description of Acadian cases (Marshall et al., 1997).

Alter and Moshang (1993) described an 11.5-year-old boy and his 9-year and 10-month-old sister with Alstrom disease. Both had deficiency of growth hormone as indicated by deficient response to provocative tests as well as by low concentrations in frequent overnight samplings of serum growth hormone. However, the patients had advanced bone ages, normal early growth, and normal concentrations of IGF1. Glucose tolerance tests demonstrated marked elevations of insulin and glucose intolerance consistent with insulin resistance. In addition to early pigmentary degeneration of the retina and neurosensory hearing loss and obesity, the boy had acanthosis nigricans. Both were of normal intelligence.

Cohen and Kisch (1994) described 2 sisters and a brother with a possible variant form of Alstrom syndrome. The 3 sibs examined by Cohen and Kisch (1994) and a fourth sib who was not available for study presented the features incorporated in the original description of the syndrome (retinal degeneration, diabetes mellitus, and neural deafness), but all had onset much later than in previously reported patients and all were fertile, producing normal offspring, in contrast to the statement of Millay et al. (1986) who, in reviewing 15 cases of Alstrom syndrome, stated that 'no patient with Alstrom's disease, male or female, has ever been known to reproduce.' In closely studied cases, the diagnosis of diabetes was preceded by or coincided with neuropathic complaints, possibly linking the nerve deafness with a common vulnerability of the nervous system within this syndrome. Insulin resistance was suggested by elevated fasting insulin levels. The affected male became hypergonadal at a later age, consistent with late onset of components of the syndrome.

Aynaci et al. (1995) described diabetes insipidus in association with Alstrom syndrome in a 16-year-old male patient. One sib who was probably affected died at 3 years of age. Features of Alstrom syndrome included blindness from an early age, with retinal atrophy, profound obesity, and diabetes mellitus.

Awazu et al. (1997) described hepatic dysfunction in a brother and sister with Alstrom syndrome. The brother developed elevation of liver enzymes at 29 years of age. Liver biopsy showed fatty liver, lymphocytic infiltration, and piecemeal necrosis. The sister had elevated gamma-glutamyltransferase (137181) levels from the age of 10 years. She developed ascites, esophageal varices, and splenomegaly in her twenties. She died at 26 years of age and autopsy confirmed the presence of cirrhosis. Awazu et al. (1997) found reports of 2 Japanese patients with Alstrom syndrome who had liver cirrhosis. Liver involvement in Alstrom syndrome appears to have been first described by Connolly et al. (1991).

Marshall et al. (1997) described a large Acadian kindred with 8 patients with Alstrom syndrome, ranging in age from 4 to 26 years at the time of clinical assessment. The affected individuals came from 5 nuclear families within this kindred and were descendants of a common ancestral pair. The single ancestral pair was shared by all 10 parents of the 5 sibships. The phenotype included early childhood retinopathy, progressive sensorineural hearing loss, truncal obesity, and acanthosis nigricans. In addition, hyperinsulinemia and hypertriglyceridemia with normal cholesterol levels were observed in most affected individuals tested. Noninsulin-dependent diabetes mellitus (NIDDM) and growth retardation appeared to be age-related manifestations that occurred after adolescence. Younger affected children were not overtly hyperglycemic and were normal or above average height for age. Of the 8 children, 4 had scoliosis, 2 had had infantile cardiomyopathy, 2 were hypothyroid, 1 had hepatic dysfunction and was hypertensive, and 4 developed asthma. Seven of the 8 exhibited developmental delay. All subjects tested showed advanced bone age. Marshall et al. (1997) reviewed 49 cases of Alstrom syndrome reported since the first description by Alstrom et al. (1959). The large pedigree from which the 8 individuals were derived contained at least 10 other cases of Alstrom syndrome. Members of the kindred had previously been reported by Tremblay et al. (1993). The patients described by Alter and Moshang (1993) were also from this kindred. Marshall et al. (1997) provided a useful 'time line' (their Figure 3) for the clinical manifestations seen consistently and findings present in some but not all Alstrom syndrome patients as age progresses.

Michaud et al. (1996) described the natural history of Alstrom syndrome in 8 patients followed 2 to 22 years. Five patients in 4 families were seen between the ages of 3 weeks and 4 months with dilated cardiomyopathy, a previously unrecognized feature of the syndrome. Photophobia and nystagmus were first documented between the ages of 5 and 15 months. Electroretinogram (ERG) initially showed a severe cone impairment with mild (2 of 8) or no (6 of 8) rod involvement. Repeat ERGs obtained between ages 9 and 22 years in 4 patients revealed extinguished rod and cone responses. Obesity developed in childhood in 7 patients, in 3 before age 2 years. Hearing impairment (5 of 8) and diabetes/glucose intolerance (4 of 8) were diagnosed by the end of the first or during the second decade.

Russell-Eggitt et al. (1998) stated that 37 cases of Alstrom syndrome had been reported in the world literature since 1959. They reviewed the clinical features of 22 cases, the largest series to that time, and compared them with those of Bardet-Biedl syndrome (209900). The 22 patients had been admitted to the Great Ormond Street Hospital for Children in London during the previous 10 years. Remarkably, 18 of the 22 cases had infantile cardiomyopathy. Russell-Eggitt et al. (1998) pointed out that at their institution there was an ascertainment bias toward younger patients and especially those with pathology such as cardiomyopathy. Alstrom syndrome in childhood is difficult to recognize without the development of infantile cardiomyopathy. Indeed, the disorder is often not recognized until diabetes mellitus develops in the second or third decade. There is a severe infantile retinal dystrophy. The ERG is absent or attenuated with better preserved rod than cone function. The retinal dystrophy is progressive, with the patient's visual acuity of 6/60 or less by 10 years of age and no light perception by 20 years of age. The diagnosis of Alstrom syndrome should be considered in infantile cone and rod retinal dystrophy, particularly if the weight is above the 90th percentile (as it was in 16 of 18 cases) or if there is infantile cardiomyopathy.

Quiros-Tejeira et al. (2001) reported a patient with Alstrom syndrome with evidence of extensive hepatic disease diagnosed at 5 years of age, who subsequently developed acute liver failure and died at 8 years of age. They raised the possibility of a mitochondrial defect in this disorder.

Ozgul et al. (2007) reported 3 Turkish sisters with Alstrom syndrome who had been followed clinically for 20 years. All had early-onset retinal degeneration with no light perception, cataracts, truncal obesity, hyperlipidemia, alopecia, and hyperostosis frontalis interna. Other features included mildly increased serum cortisol, renal failure, oligomenorrhea, recurrent pulmonary infections, insulin resistance, and hepatomegaly. All had urologic anomalies, including narrowing of the ureteropelvic junctions and deformities of the calyceal system. Renal biopsy in 1 patient showed mesangial proliferative glomerulopathy with hyaline arteriosclerosis and mild interstitial fibrosis. Two developed sensorineural hearing loss. Age at onset of diabetes, blindness, and renal failure differed among the girls, suggesting the influence of other genes or environmental factors. Unusual features included pes planus, gingivitis, light yellow-brown discolored enamel on the anterior teeth, multinodular goiter, and the structural renal anomalies.

Marshall et al. (2007) stated that approximately 450 cases of Alstrom syndrome had been diagnosed since the condition was first described in 1959. They reviewed the clinical features, diagnostic criteria, and management of the disorder.

Khan et al. (2015) described the clinical ocular features of 19 consecutive children in a retrospective case series (2010-2014) before they were diagnosed with Alstrom syndrome. All of the children, referred at age 2 to 18 years (median, 3 years), were noted to have had nystagmus in the first few months of life, significant photophobia within the first year of life, and symmetric hyperopia at presentation (3.50-8.00 diopters; median 5.5). Twelve were seen at 2 to 3 years of age, at which time most had a normal or near-normal fundus appearance. ERGs, always recordable at this age (and up to age 7 years), showed cone-rod dysfunction, often with a nearly electronegative waveform. Children older than age 7 years had retinal pigment epithelium mottling typically without intraretinal pigment migration, bull's eye maculopathy, waxy disc pallor, and nonrecordable ERGs. Bilateral posterior subcapsular cataract was noted in 5 older children, aged 12 to 16 years. At initial presentation, 11 of the 19 children had one or more extraocular features typical of Alstrom syndrome (excluding obesity), but 8 of the 19 had only ophthalmic findings (excluding obesity).

Inheritance

From the pedigree data of Alstrom et al. (1959), autosomal recessive inheritance seemed likely. Goldstein and Fialkow (1973) concluded that autosomal recessive inheritance is indisputable. They described 3 affected sisters and pointed out that a slowly progressive chronic nephropathy and acanthosis nigricans are features. Diabetes mellitus in this condition is the result of resistance to the action of insulin. Target organ unresponsiveness to the action of other polypeptide hormones, including vasopressin and gonadotropins, is suspected.

Biochemical Features

Rudiger et al. (1985) demonstrated that in Alstrom syndrome cultured fibroblasts have normal insulin-receptor binding and normal insulin stimulation of both glucose uptake, an early effect, and RNA synthesis, a late effect.

Lee et al. (2009) described an 18-month-old Taiwanese boy with Alstrom syndrome, in whom they identified a 19-bp deletion in exon 16 of the ALMS1 gene that had previously been found in another Taiwanese family with Alstrom syndrome (Marshall et al., 2007). The boy, who was obese but had normal insulin and glucose levels at 9 months of age, was begun on calorie restriction; over the next 9 months, his body mass index decreased from 25.0 to 20.7 and at 18 months of age his insulin and glucose levels remained normal. Lee et al. (2009) suggested that hyperinsulinemia is a secondary event in Alstrom syndrome that can be prevented with early treatment.

Mapping

As a result of a linkage study in a large French Acadian kindred with Alstrom syndrome and because of evidence of founder effect, Collin et al. (1997) were able to use homozygosity mapping to identify the disease locus. In a genomewide screen, haplotype sharing for a region on chromosome 2 was observed in all affected individuals. Two-point linkage analysis resulted in a maximum lod score of 3.84 at theta = 0.00 for marker D2S292. By testing additional markers, the disease gene was localized to a 14.9 cM region on 2p14-p13 (see Figure 3 of Collin et al., 1997). In a North African family in Algeria, Macari et al. (1998) refined the localization of the Alstrom syndrome locus to 2p13-p12, reducing the genetic interval to 6.1 cM. Collin et al. (1999) confirmed the mapping to 2p13 by performing a linkage study in 12 additional families. A maximum 2-point lod score of 7.13 (theta = 0.00) for marker D2S2110 and a maximum cumulative multipoint lod score of 9.16 for marker D2S2110 were observed. Meiotic recombination events localized the critical region containing the ALMS1 locus to a 6.1-cM interval flanked by markers D2S327 and D2S286.

Molecular Genetics

Collin et al. (1999) excluded the transforming growth factor-alpha gene (190170) as a candidate for Alstrom syndrome.

In affected members of 6 unrelated families with Alstrom syndrome, Collin et al. (2002) identified homozygous or compound heterozygous mutations in the ALMS1 gene (see, e.g., 606844.0001-606844.0003). The authors suggested that the ALMS1 gene probably interacts with genetic modifiers, as subsets of affected individuals present with additional features such as dilated cardiomyopathy (Michaud et al., 1996), hepatic dysfunction (Connolly et al., 1991), hypothyroidism (Charles et al., 1990), male hypogonadism, short stature, and mild to moderate developmental delay, and with secondary complications normally associated with type II diabetes, such as hyperlipidemia and atherosclerosis.

Hearn et al. (2002) studied an individual with Alstrom syndrome carrying a familial balanced reciprocal chromosome translocation involving the previously implicated Alstrom critical region: 46,XY,t(2;11)(p13;q21)mat. They postulated that this individual was a compound heterozygote, carrying one copy of the gene disrupted by the translocation and the other copy disrupted by an intragenic mutation. They mapped the 2p13 breakpoint on the maternal allele to a genomic fragment of 1.7 kb which contained exon 4 and the start of exon 5 of the ALMS1 gene; in the paternal copy of the gene, they detected a frameshift mutation. In 7 affected families, Hearn et al. (2002) detected 6 different truncating mutations in the ALMS1 gene (see, e.g., 606844.0004-606844.0006). Hearn et al. (2002) stated that ALMS1 was the first autosomal recessive human disease gene to be identified as a result of a balanced reciprocal translocation.

Marshall et al. (2007) identified a total of 79 mutations in the ALMS1 gene, including 55 novel mutations, among 250 individuals with a clinical diagnosis of Alstrom syndrome from 206 unrelated kindreds. There were 32 mutations in exon 16, 19 mutations in exon 10, and 17 mutations in exon 8, suggesting that these regions represent mutation hotspots. The most common allele was a 1-bp deletion (10775delC; 606844.0005), identified in 12% of mutated alleles. Common haplotypes were observed in kindreds of English descent who carried this allele, suggesting a founder effect. A genotype-phenotype correlation analysis in a subset of 58 patients found a trend for disease-causing variants in exon 16 and a more severe phenotype. These patients tended to have onset of retinal degeneration before age 1 year (p = 0.02), urologic dysfunction (p = 0.02), dilated cardiomyopathy (p = 0.03), and diabetes (p = 0.03). A significant association was found between alterations in exon 8 and absent, mild, or delayed renal disease (p = 0.0007).

In 3 Turkish sisters with Alstrom syndrome, Ozgul et al. (2007) identified a homozygous mutation in the ALMS1 gene (606844.0007).

In 2 cousins with Alstrom syndrome from a consanguineous Turkish pedigree, Taskesen et al. (2012) identified homozygosity for insertion of a novel Alu retrotransposon into exon 16 of the ALMS1 gene (606844.0008). The severely affected male proband was totally blind and had bilateral sensorineural hearing loss, truncal obesity, short stature, mild hypertension, hypogonadism, insulin resistance, hyperinsulinemia, type 2 diabetes mellitus, hyperlipidemia, subclinical hypothyroidism, left ventricular hypertrophy, hepatosplenomegaly, and renal failure; he died at 14 years of age of multiple organ failure after an episode of acute gastroenteritis. He had 4 older brothers who had died of unknown causes within the first year of life. His 6-year-old female cousin developed vision loss and obesity in early childhood and had hypertriglyceridemia but otherwise normal hepatic, pulmonary, cardiac, and renal function and normal hearing. She had an older brother who had died at 6 months of age from unknown causes. The ALMS1(Alu) allele was detected in 2 (6.9%) of 29 unaffected individuals from the same Turkish village as the affected pedigree, but was not found in 50 unrelated Turkish controls. No clinical features consistent with Alstrom syndrome had been reported in previous generations of the pedigree, and no other affected individuals were identified in the village.

Animal Model

Collin et al. (2005) generated a mouse model of Alstrom syndrome using an Alms1 gene-trapped ES cell line. Alms1 -/- mice developed features similar to human patients with ALMS, including obesity, hypogonadism, hyperinsulinemia, retinal dysfunction, and late-onset hearing loss. Insulin resistance and increased body weight were apparent at 8 to 12 weeks of age, with hyperglycemia manifesting at 16 weeks of age. Alms1 -/- mice displayed abnormal auditory brainstem responses after 8 months of age. Diminished cone ERG b-wave response was observed early, followed by the degeneration of photoreceptor cells. Electron microscopy revealed accumulation of intracellular vesicles in the inner segments of photoreceptors, whereas immunohistochemical analysis showed mislocalization of rhodopsin (RHO; 180380) to the outer nuclear layer. Collin et al. (2005) suggested that ALMS1 may play a role in intracellular trafficking.

Li et al. (2007) studied a mouse model of Alstrom syndrome in which the Alms1 protein was prematurely terminated at 2,130 amino acids. Primary fibroblasts and kidney cells from homozygous mutant mice expressed both mutant mRNA and protein, and they showed normal primary cilia and normal localization of the mutant protein. Homozygous mutant mice increased in weight faster than wildtype mice due to increased fat mass, and they had abnormal blood lipid chemistry, defective sperm formation, and defective rhodopsin transport in the retina. By 6 months of age, homozygous mutant mice developed multiple dilated cortical tubules, and older animals showed loss of cilia from kidney proximal tubules, which was associated with foci of apoptosis or proliferation.