Alstrom Syndrome

Alstrom syndrome (ALMS), a rare autosomal recessive condition due to mutations in the ALMS1 gene located on the second chromosome, is characterized by progressive multisystem dysfunction in homozygous individuals while heterozygous individuals are asymptomatic [1] [2] [3] [4]. The clinical presentation is variable in onset as well as severity even in individuals belonging to the same family [5].
Symptoms related to different organ systems appear in childhood and progress with age.

• Ocular: Nystagmus and photophobia appear early with complete loss of vision by the second decade of life [6]. Other ocular manifestations include bilateral subcapsular cataracts, optic disc pallor with dystrophy of the cones and rods.

• Otological: Bilateral sensorineural hearing loss starting in childhood or adulthood and progressing to moderate-to-severe hearing loss is noted in a majority of the affected individuals [7] [8]. There may also be episodes of otitis media accompanied by a conductive hearing loss in children [5].

• Endocrine/metabolic: Birth weight of children with ALMS is normal but weight gain starts early in infancy and obesity is a common problem [3] [5]. Hyperinsulinemia with insulin resistance, acanthosis nigricans, and hypertriglyceridemia start developing in childhood or during adolescence, or adulthood [5]. Pancreatitis secondary to severe hypertriglyceridemia has been reported [9] [10]. As a result of metabolic changes, a majority of individuals with ALMS suffer from cardiac and renal impairment and may even present with sudden onset of congestive heart failure. Testicular atrophy and small genitalia have been reported in males while hyperandrogenism and hirsutism with menstrual irregularities and precocious puberty have been reported in females with ALMS [5] [11].

• Liver: Hepatic dysfunction is noticed as an asymptomatic increase in the levels of serum transaminases, followed by hepatosplenomegaly, a possible presence of hepatocellular adenoma [12], and the progression to cirrhosis and its sequelae.

• Renal: Progressive polyuria, renal tubular acidosis with hypertension, urinary tract infections, obstructive uropathy and instability of detrusor muscle can occur leading to end-stage renal disease (ESRD) in adolescence [5] [13].

• Respiratory: Recurrent respiratory tract infections result in problems ranging from chronic rhinosinusitis to chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).

• Neurological: Affected individuals have normal intelligence with delayed motor and intellectual milestones, balance changes [14] [15], speech problems and cerebellar anomalies [16].

Although growth spurt is normal in early childhood, it plateaus off and individuals with ALMS usually have a short stature, round face, thick ears, frontal alopecia, abnormal and discolored dentition, scoliosis, flat feet and short, fat fingers and toes.

Mortality in young ALMS patients is due to dilated cardiomyopathy while in older patients is mainly due to renal failure [5] [17].

The diagnosis of ALMS is based on the typical clinical presentation, although, occasionally variable phenotypic expression can delay the diagnosis [2] [3]. Cone electroretinography reveals weak cone activity in infancy with severely diminished responses and cone dystrophy on full-field electroretinography by 3 years of age. Optical coherence tomography (OCT) imaging has been used to demonstrate macular thinning and developmental arrest [18]. Laboratory tests help to detect elevated blood sugar levels with hypertriglyceridemia, elevated hepatic transaminases, abnormal renal function tests, albuminuria, low levels of testosterone, elevated gonadotropins, low levels of growth hormone, abnormal levels of insulin-like growth factors [19] [20], elevated leptin levels [20], and secondary or subclinical hypothyroidism.

Molecular genetic analysis is used to confirm the diagnosis [21] [22] [23].

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21. Collin GB, Marshall JD, Ikeda A, et al. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome. Nat. Genet. 2002;31:74–78.
22. Hearn T, Renforth GL, Spalluto C, et al. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alström syndrome. Nat. Genet. 2002;31:79–83.
23. Marshall JD, Hinman EG, Collin GB, et al. Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alström syndrome. Hum. Mutat. 2007;28:1114–1123.