Rare diseases (affecting fewer than 1 in 2,000 people) are an emerging global public health priority. Given their high heterogeneity and the need to provide individualized medicine for small patient populations, they have become a challenge for healthcare systems and biopharmaceutical research. This post is about one of these diseases that affect young children from infancy: Alström syndrome. Alström syndrome (AS) , one on which we work from the consortium OLIGOFASTX consortium to achieve an effective treatment with oligonucleotides. .
The Alström syndrome is characterized by dystrophy of the cones (cells that allow daytime vision and color vision) and rods (cells that allow night vision or vision in dimly lit places) in the retina. The retina is the inner eye tissue on which images are projected and where light signals are converted into electrical impulses that reach the brain and generate vision.
But this syndrome is also associated with other disorders in the same person, a situation known as comorbidity. In particular, hearing loss, hypertriglyceridemia and obesity, hyperinsulinemia, type 2 diabetes mellitus, dilated cardiomyopathy (DCM), multiorgan fibrosis, hypogonadism/hyperandrogenism, chronic respiratory disease, and progressive renal and hepatic dysfunction are common.
It is, therefore, a disease that is genetically transmitted and presents a complex set of comorbidities to manage and treat, especially when it affects the very young.
Mutations in the ALMS1 gene: responsible for the syndrome
Alström syndrome was described in 1959 by Carl Henry Alström and Bertil Hallgren. Today, it is a paradigm considered a rare disease, since its frequency has been estimated at about one case per 100,000 newborns. However, the clinical manifestations of this syndrome do not usually present at birth because they appear in an evolutionary manner.
This fact, together with its low frequency, makes it a very little known syndrome, which also causes a delay in its diagnosis. A delay that has important repercussions on the quality of life and life expectancy of those affected, especially when they are mistakenly diagnosed with one of the syndromes that have very similar clinical characteristics and are more frequent.
Alström syndrome is caused by mutations in the ALMS1 gene and is transmitted as an autosomal recessive trait. Diagnosis is made on the basis of observed clinical features, usually without genetic confirmation. The identification of 2 mutated alleles, or the mutated ALMS1, with typical clinical features, would confirm the diagnosis.
Progressive but rapid and complex symptoms
Clinically, Alström syndrome is characterized by the fact that the symptoms tend to appear in a certain order. The first signs may be dilated cardiomyopathy and/or visual disturbances that may occur in the first months of life.
But it can also be accompanied by other complications:
- Cone and rod dystrophy with nystagmus, photophobia and progressive impairment of central and peripheral vision may progress to blindness at about 7 years of age, although residual vision may be preserved until about 25 years of age.
- Retinitis pigmentosa (another disease under study within the OLIGOFASTX project) can be evident as early as the first year of life.
- Moderate obesity may begin in the first or second year of life, although it usually begins in adolescence.
- Progressive sensorineural deafness begins around 4 to 8 years of age.
- Glucose intolerance may begin in adolescence and by the middle of the second decade of life it develops into insulin-dependent diabetes mellitus. Cases of onset in children as young as two years of age have been reported.
- Hypogonadism presents with normal secondary sexual development. Males present with primary testicular failure and females with menstrual irregularities.
- Chronic kidney disease presents with tubular dysfunction and progresses to renal failure between the second and fourth decades of life.
Other accompanying findings are: hypothyroidism, acanthosis nigricans, scoliosis, short stature, dyslipidemia: hypertriglyceridemia, hypercholesterolemia, hyperuricemia.
Diagnosis and treatment
The diagnosis of the disease is primarily clinical, and the characteristic features occur in infants or young adults.
There is no specific curative treatment for the disease. The goal of treatment is to correct or alleviate some of the symptoms that appear and to control diabetes mellitus through diet and exercise with or without antidiabetic medication. The use of hearing aids can help to cope with hearing loss.
A proper assessment and management of these patients requires an interdisciplinary approach involving ophthalmologists, endocrinologists, occupational therapists, psychologists, nurses and social workers.
The company conducting the main research in the field of this disease in the OLIGOFASTX project is Sylentis.