Alstrom Syndrome with a Mutation in Exon 8 ( C . 4746 C > A ) of Alstrom Syndrome Protein 1 Gene : The First Case Report and Literature Review

Alström syndrome (AS) is a rare, autosomal recessive disorder characterized by progressive cone-rod dystrophy, childhood obesity, sensorineural hearing impairment, type 2 diabetes, hypogonadism, and additional abnormalities. Herein we report a 29-year-old man with progressive cone-rod dystrophy, hearing impairment, liver cirrhosis, bilateral cryptorchidism with hypergonadotropic hypogonadism, and type2 diabetes. He had severe insulin resistance and required high-dose insulin to treat his hyperglycemia. Genetic testingrevealed a mutation in exon8 (c.4746C > A) of the Alström syndrome protein1 (ALMS1) gene and this is the first report of this mutation in AS.It is difficult to lead to correct diagnosis without genetic test, and physicians should suspect AS when patients show early onset visual dysfunction, obesity, or type 2 diabetes. *Corresponding author: Masayasu Yoneda, 1-2-3 Kasumi Minami-ku Hiroshima, Japan, 734-8551, Tel: +81-82-257-5196; Fax: +81-82-255-7360; E-mail: masayone17@hiroshima-u.ac.jp Citation: Yoneda, M., et al. Alstrom Syndrome with a Mutation in Exon8 (C.4746C > A) of Alstrom Syndrome Protein 1 Gene: The First Case Report and Literature Review. (2017) J diab Obes 4(2): 14.

hyperglycemia and undergo medical detailed examinations for multi-organ dysfunction from childhood.
He was born at full-term via a normal delivery, with a birth weight of 2680 g. Photophobia was noted at the age of 1, and he gradually lost visual acuity. Hecompletely lost his eyesight at the age of 15 due to cone-rod dystrophy. He had also presented with obesity since the age of 2, type2 diabetes and sensorineural hearing impairment since the age of 10, and liver dysfunction and thrombocytopenia since the age of 27. He was treated with antidiabetic agents from diagnosis and his glycemic control was around HbA1c 7%.
At the age of 29, he went to a general hospital because of progressing hyperglycemia. Liver cirrhosis, splenomegaly, and an esophageal varixwere subsequently diagnosed at the hospital. Initially, drug-induced hepatitis was suspected; hence, all antidiabetic agents(metformin, glimepiride, and voglibose) were stopped, and insulin therapy with 4 injections/daywas initiated. Although he used more than 100 U/day of insulin, his glycemic control remained poor. He also had diabetic complications; diabetic kidney disease, diabetic retinopathy and neuropathy. In addition, hypergonadotropic hypogonadism was identified. He was referred to our hospital for hyperglycemia treatment and undergoing medical detailed examinations for multi-organ dysfunction.
The patient's parents were fifth-degree relatives;hence, we suspected some genetic disorders (figure 1). He had a healthy, unaffected older brother, and no relatives possessedsimilar diseases. On a physical examination in our hospital, he was 154.5 cm in height, 46.0 kg in weight, and his body mass index was 19.3 kg/m 2 . Body temperature was 36.3°C. He reported no alcohol consumption. Bilateral cryptorchidism was evident in the absence ofpolydactyly, neurological dysfunction, and skin tags. No splenomegaly, jaundice, or edemas were observed. Laboratory data (Table 1) showed elevated liver enzyme levels, pancytopenia, and hypoalbuminemia. He tested negative for hepatitis B surface (HBs) antigen, hepatitis C virus (HCV) antibody, and autoantibodies [anti-nuclear antibody (ANA) and anti-mitochondrial M2 antibody (AMA-M2)]. Glycemic control was poor (HbA1c 8.8%). CRP elevation was likely due to aspiration revealed in the swallowing test. Hypergonadotropic hypogonadism and cryptorchidism were also observed. Hepatatrophy, hepatosteatosis, splenomegaly, esophageal varix, and stomach ulcer were identified by contrast-enhanced computed tomography (CT) and upper gastrointestinal endoscopy. Fund us copy revealed cone-rod dystrophy. Audiometry revealed bilateral sensorineural hearing impairment. Ohwaki's intelligence test showed no intellectual disturbance or mental developmental delay. Insulin dose was titrated upwards to (3.0 U/kg)with concurrent diet (1500 kcal, protein 50 g/day) and exercise therapy, resulting in agradual improvementin glycemic control by the fourteenth hospital day ( Figure 2) and was discharged from our hospital on the twenty-eighth hospital day. Liver biopsy was not performed, because he could not follow instructions due to the hearing impairment. Testosterone replacement therapy was not pursuedbecause he had developed secondary sexual characteristics and asymptomatic upon physical examination. We suspected some genetic disorder, especially AS, because of multi-organ dysfunction. We requested a genetic analysis to Dr. Marshall, identified a single nucleotide substitution at position 4746(6) (c.4746C > A in exon 8) and finally diagnosed AS.We obtained written informed consent for the genetic analysis from the patient and his family. This study was approved by the Hiroshima University ethical committee.

Discussion
Bardet-Biedl Syndrome (BBS) and Laurence-Moon Syndrome (LMS)are disordersrelated to AS that share the same symptoms of AS, including low vision, hearing loss, type2 diabetes, and liver dysfunction;hence, it is sometimes difficult to distinguish these syndromes from AS. This patient had no paraplegia and no mental retardation, the main criteria for the diagnosis of LMS. He exhibited clinical diagnostic criteria of BBS, but had no polydactyly and no intellectual disturbance, characteristic symptoms of BBS. He also exhibited clinical diagnostic criteria of AS [11] , one major criteria (low vision) and fiveminor criteria (insulin resistance and Type 2 diabetes mellitus, hearing loss, hepatic dysfunction, short stature and hypogonadism). Therefore, we suspected AS, and an ALMS1 mutation was identified by genetic testing.
AS is an autosomal recessive disease, and the preva- lence of AS is estimated as less than 0.001% [1] . AS results from mutations in the ALMS1 gene located on chromosome 2p13 [7] . The ALMS1 gene contains 23 exons, and 85% of mutations are present in exons 8, 10, and 16 [6] . To date, 239 different mutations have been described in ALMS1 [6] . The same mutation found in our patient has been reported in only one case [6] , and this is the first detailed case report of this mutation. ALMS1 mRNA is ubiquitously expressed inthe brain, lung, and testis.The ALMS1 protein has diverse roles in each organ [10] . It has been reported that patients with mutations in exon 16, where most mutations have been found, have more severe disease phenotypes, and that patients with mutations in exon 8 havea lower incidence of renal dysfunction [12] .
It has been reported that 70% of AS patients have type2 diabetes by 20 years of age, with a median age of onset of 16 years, and have severe insulin resistance [12] . In our patient, 3.0 U/ kg of insulin was required to improve glycemic control, because of his severe insulin resistance. Patients with AS often have much more severe insulin resistance than controls, even when matched for age and body composition [13] . Insulin resistance was possibly caused by hepatosteatosisor silent liver damage, obesity, and attenuationof insulin signalsby aging. In addition, more than half of female AS patients demonstrate various signs of polycystic ovary syndrome (PCOS) orhyperandrogenism [14] . Hence, obesity caused by those diseases sometimes contributes insulin resistance [15,16] . In our patient, severe insulin resistance was supposed to becaused by liver cirrhosis and aspiration pneumonia. Several studies demonstrated that metformin and thiazolidine, insulin-sensitizers,and exenatide, a glucagon-like peptide-1 (GLP-1) analogue, were effective forthe treatmentof diabetes in patients with AS [14,17,18] . In our patient, isolated insulin therapy was applied because of liver cirrhosis.
There are various phenotypes of liver dysfunction in patients with AS.Liver dysfunction begins with clinically silent elevation of transaminases and hepatosteatosis, and some patients can progress to liver fibrosis or cirrhosis [19][20][21][22][23] . Inflammatory changes resulting in fibrosis do not appear to be autoimmune related, because patients test negative for antinuclear antibodies and other typical markers of autoimmune hepatitis [24] . Phenotypic variation of disease progression in AS patients carrying the same mutation suggests that there might be some interplay between multiple potential genetic modifiers and environmental or infectious exposures. In our patient, inspite of cirrhosis suspected by hepatatrophy and esophageal varix identified by CT and upper gastrointestinal endoscopy, the cause of cirrhosis was not revealed since liver biopsy was not pursued. He had silent elevation of transaminases since the age of 27, so the best etiologic evidence of his liver cirrhosis was the presence of elevated transaminases and hepatosteatosis.
Although AS is very rare, physicians should suspect AS when patients show early onset visualdysfunction, obesity, or type2 diabetes.We believe that early diagnosis may provide better medical treatment, lengthen survival, and improve quality of life.