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

Fig. 1

Clinical photos and genotypes of patients 1 and 2, each at the age of 15 years. Note the common feature of abdominal and truncal obesity, and loss of fat mass in the gluteal region. Both have gynecomastia, kyphosis, and acanthosis nigricans in abdominal skin flexures. (a, b) patient 1, (c, d) patient 2. (e) A heterozygous two base pair deletion in exon 16, c.10568_10569delAT; p.H3523Xfs17, was identified in patient 1. (f) Heterozygous single base pair duplications in exon 8, (c.3163dupG; p.E1055GfsX4 and c.4156dupA; p.T1386NfsX15), were identified in patient 2. All mutations result in a premature termination signal in ALMS1. Black arrows demarcate the site of the frameshift mutations. ALMS, Alström syndrome.

Fig. 2

Epileptic spike and wave discharges monitored with EEG of patient 2 at the age of 8 years. (a)(b)(c) represent three separate EEG measurements.