Paula and Bobby
Parents of Lillie
Alstrom syndrome; ALMS
What is Alstrom syndrome; ALMS?
Alstrom syndrome; ALMS is a rare disease. It is also known as Alss.
This syndrome is variable in its expression and it is not absolutely certain that all the references cited refer to the same condition, although they are very similar. Mental retardation does not usually occur but has been described (one patient has even been seriously handicapped - Kuburovic et al., (2013); visual problems occur soon after birth and might end in blindness due to a retinopathy (pigmentary) or cataracts. Photophobia and a cone-rod dystrophy may be the presenting visual problems. A neural deafness occurs. Obesity, short stature and hypogonadism are frequent. Testicular biopsy shows small hyalinized tubules, and there is a low plasma testosterone with elevated urinary gonadotrophin. Diabetes mellitus is common and may be of a specific type with a post-receptoral defect. There is significant insulin resistance. Two of Alstrom's original patients died from a progressive azotemia. Quiros-Tejeira et al., (2001) reported a 8 year old Chinese female with features of the condition who developed liver disease at 5 years of age and died of acute liver failure. Hyperlipidaemia and hypothyroidism may also be a feature in some cases. At post mortem one had a form of glomerulosclerosis. Acanthosis nigricans is a further feature of the condition. Michaud et al., (1996) report eight patients and provide a good review. Five of the patients were found to have a dilated cardiomyopathy between the ages of three weeks and four months. Photophobia and nystagmus were the presenting ocular symptoms occurring between the age of five months and fifteen months. Obesity developed during childhood in seven and in three as early as two years. Five were deaf and four developed diabetes before the age of 20. The authors suggest that cardiomyopathy is a feature of the condition and note that Warren et al., (1987) reported two brothers with Alstrom syndrome who had heart failure as a result of dilated cardiomyopathy at the ages of 36 and 37. In a family with four affected siblings the expression of the cardiomyopathy appeared extremely variable (Hoffman et al., 2005).
Deeble et al., (2000) clearly set out the clinical features of Alstrom syndrome which consist of progressive visual impairment presenting in the first six months of life with photophobia and nystagmus, advancing to a cone-rod dystrophy and registered blindness in the second decade. Truncal obesity and acanthosis nigricans are evident before five years but become more obvious after puberty. Male external genitalia remain small. All patients are of short stature by the age of 8 years but none manifest diabetes mellitus, although this has been previously reported as a common feature. Sensorineural deafness presents late in the first decade. Renal failure frequently develops during the third decade. A dilated cardiomyopathy can occur at any age and often spontaneously improves. It may present in the first year of life before other disease features (Long et al., 2015). Three sibs, with a mutation, all had multinodular goiters and 2 had hyperthyroidism (Ozgul et al., 2007).
Marshall et al., (1997) provide clinical details of a large Acadian kindred emphasising the variability of the condition and the association with cardiomyopathy, hypothyroidism, hyperlipidemia (with normal cholesterol levels) and hyperinsulinemia. They also noted that an advanced bone age was observed in all subjects tested. Connolly et al., (1991) reported an 11-year-old girl with this condition who also had hepatic dysfunction, clinically similar to chronic active hepatitis. Awazu et al., (1997) also reported two sibs with hepatic dysfunction. Dyer et al., (1994) reported a 10-year-old boy with the condition, and provide a good review of the differential diagnosis with Bardet-Biedl syndrome. Note that gene sequencing might be necessary to distinguish between the two (Aliferis et al., 2012)
Bonnekoh et al., (1993) reported a 54-year-old man with acanthosis nigricans, obesity, and diabetes mellitus. He also had extra nipples and 2-3 toe syndactyly. Eye findings were not commented on. It is not certain whether this case falls into the Alstrom category. Two sibs reported by Louw et al., (2014) with a mitogenic form of dilated cardiomyopathy had homozygous mutations in ALMS1, the gene responsible for Alstrom syndrome
Collin et al., (1997), (1999) mapped the gene to 2p12-13 in a large inbred French Acadian kindred. Macari et al., (1998) refined this linkage in a North African family. Zumsteg et al., (2000) reported a Barzilian family with three affected sibs and parental consanguinity where linkage to 2p12-13 was consistent. Colin et al., (2002) and Hearn et al., (2002) demonstrated mutations in the ALMS1 gene. This does not share significant sequence homology with other genes reported so far. Further mutations were reported by Titomanlio et al., (2004). There is an excellent review of 182 cases by Marshall et al., (2005) and another by Marshall et al., (2007).
Brofferio et al. (2017) described clinical characteristics in 38 patients with Alstrom syndrome. Clinical symptoms were decreased visual acuity (37), mild to severe hearing loss (29), overweight (4) or obesity (29), type 2 diabetes (14), hypertension (7), pre-hypertension (11), hypertriglyceridemia (20), hypercholesterolemia (11), low glomerular filtration rate (11), and portal hypertension (12). Cardiac features were infantile onset cardiomyopathy (13) or late onset cardiomyopathy (5). Echocardiography showed decreased ejection fraction, thickened mitral valve, left ventricular hypertrophy, left ventricular enlargement, and right atrial enlargement.
* This information is courtesy of the L M D.
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What gene changes cause Alstrom syndrome; ALMS?
The syndrome is inherited in the following inheritance pattern/s:
Autosomal Recessive - Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms but have a 25% chance of passing the copies of the gene mutations onto each of their children.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.
OMIM Number - 203800 (please check the OMIM page for updated information)
The syndrome can be caused by mutations in the following gene/s location/s:
ALMS1 - 2p13.1
What are the main symptoms of Alstrom syndrome; ALMS?
The typical symptoms of the syndrome are:
Hypertension, Hypertriglyceridemia, Hypertrichosis, Kyphosis, Hyperinsulinemia, Hyperostosis frontalis interna, Short stature, Hepatomegaly, Hepatic steatosis, Hyperuricemia, Hypertrophic cardiomyopathy, Gingivitis, Acanthosis nigricans, Visual impairment, Hypothyroidism, Hypergonadotropic hypogonadism, Cognitive impairment, Glomerulopathy, Global developmental delay, Gynecomastia, Growth hormone deficiency, Tubulointerstitial nephritis, Recurrent respiratory infections, Pulmonary fibrosis, Truncal obesity, Pulmonary arterial hypertension, Respiratory failure, Splenomegaly, Renovascular hypertension, Chronic active hepatitis, Round face, Type II diabetes mellitus, Recurrent pneumonia, Scoliosis, Vesicoureteral reflux, Renal insufficiency, Progressive sensorineural hearing impairment, Subcapsular cataract, Pes planus, Pigmentary retinopathy, Otitis media, Nystagmus, Sensorineural hearing impairment, Obsessive-compulsive behavior, Autosomal recessive inheritance, Photophobia, Portal hypertension, Polycystic ova
How does someone get tested for Alstrom syndrome; ALMS?
The initial testing for Alstrom syndrome; ALMS can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
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