A novel ALMS1 splice mutation in a non-obese juvenile-onset insulin-dependent syndromic diabetic patient

Abstract

Insulin-dependent juvenile-onset diabetes may occur in the context of rare syndromic presentations suggesting monogenic inheritance rather than common multifactorial autoimmune type 1 diabetes. Here, we report the case of a Lebanese patient diagnosed with juvenile-onset insulin-dependent diabetes presenting ketoacidosis, early-onset retinopathy with optic atrophy, hearing loss, diabetes insipidus, epilepsy, and normal weight and stature, who later developed insulin resistance. Despite similarities with Wolfram syndrome, we excluded the WFS1 gene as responsible for this disease. Using combined linkage and candidate gene study, we selected ALMS1, responsible for Alströ m syndrome, as a candidate gene. We identified a novel splice mutation in intron 18 located 3 bp before the intron-exon junction (IVS18-3T4G), resulting in exon 19 skipping and consequent frameshift generating a truncated protein (V3958fs3964X). The clinical presentation of the patient significantly differed from typical Alströ m syndrome by the absence of truncal obesity and short stature, and by the presence of ketoacidotic insulin-dependent diabetes, optic atrophy and diabetes insipidus. Our observation broadens the clinical spectrum of Alström syndrome and suggests that ALMS1 mutations may be considered in patients who initially present with an acute onset of insulin-dependent diabetes.

The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey

“…Ten were nonsense mutations, nine were frameshift mutations, and one intronic splice site mutation identified which was previously reported to be pathogenic 37 .…”

“…Eight novel and 12 previously reported 12, 16, 23, 27, 28, 31, 37 mutations were identified in exons 8, 10, 11, 16 and intron 18 in 25 kindreds (Table 1 and 2). …”

Long-term clinical follow-up and molecular testing for diagnosis of the first Tunisian family with Alström syndrome

“…However only 12 Arabic patients have been reported [Marshall et al, 2015; Aldahmesh et al, 2009; Sanyoura et al, 2014]. For the North African patients, four mutations were identified in six patients (c.906del in exon 5, c.3066T>A and c.5929C>T in exon 8 and c.10124C>G in exon 14) [Marshall et al, 2015].…”

“…Three patients presented a splice mutation. The first patient was a Lebanese boy who was diagnosed with type I diabetes (T1D) at the age of 13 with progressive vision loss, optic atrophy, bilateral hearing loss and neurological m anifestations but without cardiomyopathy, obesity and short stature [Sanyoura et al, 2014]. The mutation identified was IVS18-3T>G (c.11876-3T>G).…”

“…Their mutation was very similar to the mutation reported in the Lebanese boy. Both mutations fully abolish the consensus acceptor site resulting in complete skipping of exon 19 [Aldahmesh et al, 2009, Sanyoura et al, 2014]. .…”