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Differences in the clinical spectrum of two adolescent male patients with Alstrom syndrome.

ABSTRACT: Alström syndrome is a rare disorder typified by early childhood obesity, neurosensory deficits, cardiomyopathy, progressive renal and hepatic dysfunction, and endocrinological features such as severe insulin resistance, type 2 diabetes, hyperlipidemia, and hypogonadism. Widespread fibrosis leads to multiple organ failure. Mutations in ALMS1 cause Alström syndrome. Two age-matched, unrelated adolescent males of Serbian descent with Alström syndrome underwent an extensive workup of blood chemistries, and ophthalmological, audiological, and genetic evaluations. Although both showed typical features of Alström syndrome in childhood, several differences were observed that have not been reported previously. Patient 1 was first studied at the age of 13 years for multisystemic disease and re-evaluated at the age of 15.5 years. Patient 2 is a 15-year-old boy who presented at birth with epilepsy and psychomotor developmental delay and generalized tonic-clonic seizures with severe cognitive impairment, features not documented previously in this syndrome. Sequencing analysis indicated two novel ALMS1 mutations in exon 8: p.E1055GfsX4 and p.T1386NfsX15. Metabolic and physiological similarities were observed in both patients, including severe insulin resistance, and truncal obesity with fat loss suggestive of partial lipodystrophy, supporting evidence for a role for ALMS1 in adipose tissue function. The unusual phenotypes of clonic-tonic seizures and severe cognitive abnormalities and lipodystrophy-like adiposity pattern have not been documented previously in Alström syndrome and may be an under-reported abnormality.

SUBMITTER: Kuburovic V

PROVIDER: S-EPMC3619948 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Differences in the clinical spectrum of two adolescent male patients with Alström syndrome.

Kuburović Vladimir V Marshall Jan D JD Collin Gayle B GB Nykamp Keith K Kuburović Nina N Milenković Tatjana T Rakić Sanja S Djuric Milena M Ječmenica Jovana J Milenković Svetislav S Naggert Jürgen K JK

Clinical dysmorphology 20130101 1

Alström syndrome is a rare disorder typified by early childhood obesity, neurosensory deficits, cardiomyopathy, progressive renal and hepatic dysfunction, and endocrinological features such as severe insulin resistance, type 2 diabetes, hyperlipidemia, and hypogonadism. Widespread fibrosis leads to multiple organ failure. Mutations in ALMS1 cause Alström syndrome. Two age-matched, unrelated adolescent males of Serbian descent with Alström syndrome underwent an extensive workup of blood chemistri ...[more]

PMID: 23188138

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Project description:Alström syndrome (ALMS) is an autosomal recessive disease characterized by multiple organ involvement, including neurosensory vision and hearing loss, childhood obesity, diabetes mellitus, cardiomyopathy, hypogonadism, and pulmonary, hepatic, renal failure and systemic fibrosis. Alström Syndrome is caused by mutations in ALMS1, and ALMS1 protein is thought to have a role in microtubule organization, intraflagellar transport, endosome recycling and cell cycle regulation. Here, we report extensive phenotypic and genetic analysis of a large cohort of Turkish patients with ALMS. We evaluated 61 Turkish patients, including 11 previously reported, for both clinical spectrum and mutations in ALMS1. To reveal the molecular diagnosis of the patients, different approaches were used in combination, a cohort of patients were screened by the gene array to detect the common mutations in ALMS1 gene, then in patients having any of the common ALMS1 mutations were subjected to direct DNA sequencing or next-generation sequencing for the screening of mutations in all coding regions of the gene. In total, 20 distinct disease-causing nucleotide changes in ALMS1 have been identified, eight of which are novel, thereby increasing the reported ALMS1 mutations by 6% (8/120). Five disease-causing variants were identified in more than one kindred, but most of the alleles were unique to each single patient and identified only once (16/20). So far, 16 mutations identified were specific to the Turkish population, and four have also been reported in other ethnicities. In addition, 49 variants of uncertain pathogenicity were noted, and four of these were very rare and probably or likely deleterious according to in silico mutation prediction analyses. ALMS has a relatively high incidence in Turkey and the present study shows that the ALMS1 mutations are largely heterogeneous; thus, these data from a particular population may provide a unique source for the identification of additional mutations underlying Alström Syndrome and contribute to genotype-phenotype correlation studies.

Project description:PurposeAlström syndrome (AS) is a rare monogenic autosomal recessively inherited disorder characterized by cone rod dystrophy and multiple organ dysfunction. Mutations in the Alström syndrome 1 (ALMS1) gene have been found to be causative for AS. The purpose of this study was to identify ALMS1 mutations and to assess the clinical features of Chinese patients with AS.MethodsDetailed ocular and laboratory examinations were performed. Peripheral blood samples were collected from patients and their parents. Genomic DNA was extracted with a Qiagen kit. Exons and exon/intron junctions of ALMS1 were amplified with polymerase chain reaction (PCR) and screened for mutations with Sanger sequencing. The results were compared with the ALMS1 transcript to exclude polymorphisms and confirm pathogenic mutations.ResultsSeven patients from five unrelated non-consanguineous families were diagnosed with AS. All patients had cone rod dystrophy with impaired visual acuity, photophobia, and nystagmus. Other clinical features, including sensorineural hearing loss, truncal obesity, insulin resistance, type 2 diabetes mellitus, renal and hepatic dysfunction, hyperlipidemia, hypothyroidism, mental retardation, acanthosis nigricans, and scoliosis, were present. Sequencing revealed two novel mutations, p.N3150Kfs2X and p.V3154Xfs, in patient 1; one novel mutation, p.N3672Ifs11X, and one previously reported nonsense mutation, p.R3703X, in patient 2; novel mutations p.S2479X and p.R3611Efs7X in patient 3; one novel homozygous mutation, p.S695X, in patients 4 and 5; and two novel mutations, p.H688HfsX and p.Q3147Qfs2X, in patients 6 and 7. These mutations were not present in 100 unrelated healthy Chinese control subjects. The patients' parents were heterozygous carriers of the mutant allele.ConclusionsSeven Chinese patients with AS showed typical ophthalmic features and multiple organ dysfunction. Novel loss of function mutations in the ALMS1 gene are the underlying genetic defects.

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Differences in the clinical spectrum of two adolescent male patients with Alstrom syndrome.

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Differences in the clinical spectrum of two adolescent male patients with Alström syndrome.

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