[44] Additional Morphologic and Genetic Data in Alstrom Syndrome

C Thakral, JD Marshall, C Curtiss, AT Philip, SK Landas. Upstate Medical University, Syracuse, NY; The Jackson Laboratory, Bar Harbor, ME

Background: Alstrom Syndrome (ALMS) is a recessively inherited disorder with a complex and variable clinical spectrum. Cardiac abnormalities are known to occur in more than 60% of these patients but have not been well characterized. ALMS is caused by mutations in ALMS1 (Chr 2p13), a gene ubiquitously expressed with unknown function. ALMS1 has been implicated in ciliary function and intracellular transport, but the link between mutation of ALMS1 and development of disease is poorly understood. We report the clinical, pathological and genetic features in a Caucasian male born of non-consanguineous parents. He developed nystagmus (at 10 months), blindness, hearing loss (at 7 years), type 2 diabetes mellitus (at 7 years), obesity (BMI: 35, at 9 years), acanthosis nigricans, short stature and scoliosis. He had hypothyroidism, hypogonadism, splenomegaly, dyslipidemia, and abnormal liver and renal function tests. At 19 years of age, he presented with acute severe respiratory distress, bilateral pulmonary infiltrates and left ventricular ejection fraction of <10%. He died the following day.
Design: Autopsy was performed according to the standard protocol. Tissue was fixed in formalin and glutaraldehyde for histologic and electron microscopic examination, respectively. Mutational analysis for ALMS1 gene was performed at the Jackson Laboratory, Bar Harbor, Maine.
Results: Autopsy revealed an enlarged (420g) and hypertrophied heart (left and right ventricular free wall thickness 1.7 & 0.9 cm, respectively; and septal thickness of 2.1 cm). Histologic and ultrastructural examination showed signs of disorganized myocyte architecture, including disarray of myofibrils, intertwined hypertrophic myocytes with bizarre-shaped nuclei and moderate interstitial fibrosis. Kidneys showed focal glomerulosclerosis and interstitial fibrosis. There was florid lymphocytic thyroiditis and testicular atrophy with aspermatogenia (negative OCT3/OCT4 stain). There was evidence of acute multifocal bronchopneumonia and congestive heart failure. He carried two heterozygous mutations in ALMS1: 11316_11319delAGAG; R3772fs in exon 16 and 8164C>T ter; R2722X in exon 10.
Conclusions: This report describes previously undefined cardiac abnormalities in this rare multisystem disorder. Myofibrillar disarray is probably directly linked to ALMS1 mutation, while fibrosis in multiple organs may be a secondary phenomenon to gene alteration. Whether and how intracellular trafficking or related signals lead to cardiac dysfunction is a subject for further research.
Category: Autopsy

Wednesday, March 24, 2010 9:30 AM

Poster Session V # 17, Wednesday Morning

 

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