Research in Alström Syndrome: history and future directions

Jan D. Marshall
The Jackson Laboratory, Bar Harbor, Maine, USA

In 1959, CH Alström first described a unique autosomal recessive disorder with clinical features that were distinct from other similar disorders. Alström syndrome is particularly difficult to diagnose because it is rare, and it has a complex phenotype that evolves over time with variation of presentations. Patients often have multiple misdiagnoses, or never even receive a diagnosis in the course of their lifetime. In the 42 years between the first description of Alström syndrome and the successful cloning of the causative gene, ALMS1, very few medical papers appeared in the scientific literature.

While efforts to clone ALMS1 escalated, more researchers and physicians became intrigued by the multi-faceted nature and complex clinical spectrum of the disorder. We have collected demographic and clinical information on a worldwide sample of 223 patients with a diagnosis of Alström Syndrome. In addition to DNA for genetic investigations, we have obtained data from clinical examinations, review of medical records, standardized questionnaires, and personal interviews with physicians or appropriate family members. Information has been evaluated, computerized, and stored in a relational database. We regularly update clinical data for individual patients using information from the ongoing collection of medical records and notes. Analysis of these data has enabled a more precise description of the phenotype with respect to variability of expression and age of presentation.

The disorder is pan-ethnic, with the highest incidence occurring in individuals of Northern and Central European descent. Ninety-seven are residents of US and Canada, 47 reside in UK, and in 11 in Italy. Other countries with significant numbers of patients in this dataset are Germany (15), France (6), Taiwan (6), and Turkey (5).

We have also documented new cardiac, pulmonary, urological, neurological, and gastrointestinal phenotypes associated with Alström syndrome. Dilated cardiomyopathy in 63% of patients fell into two distinct groups: a) infant onset, before vision disturbances are noted, and b) adolescent/adult onset. Minor to severe urological dysfunction occurred in 55% of patients. Persistent and severe pulmonary symptoms occurred in 58% of patients. Twenty-three percent had gastrointestinal reflux. Neurological symptoms in 39% of patients included absence seizures, pervasive developmental abnormalities, clonic tics, and motor or language delays. We found fibrotic infiltration in multiple postmortem tissues: kidney, liver, lung, bladder, gonads, pancreas, and heart.

In 1995, Alström Syndrome International (ASI) had its beginnings. It is now an international organization offering support to patients and families, as well as researchers and physicians. ASI has been instrumental in identifying new patients and families and made possible not only the research leading to the identification of the ALMS1 gene, but also the ongoing clinical research that may lead to new therapies and better management of patients with Alström syndrome.