diabetes

Alström Syndrome

Clinical Characteristics
Ocular Features: 

Progressive failure of rods and cones begins in the first year of life and inevitably leads to blindness.  Central vision is lost first and nystagmus in early childhood results.   Photophobia can be evident in the first year of life.  Early ERGs show severe impairment of cone responses with little or no rod dysfunction.  In the second and third decades all rod and cone responses are extinguished.  Vision can be less than 20/400 by the age of 10 years and usually all light perception is lost by the beginning of the third decade.  Pale optic nerves with retinal arteriorlar narrowing and posterior subcapsular cataracts have been seen.

Systemic Features: 

This is a multisystem disease with onset in the first year of life.  Infants may have a normal birth weight but develop truncal obesity in the first year.  Hearing loss is evident in the first decade.  Insulin resistant type 2 diabetes mellitus with hyperinsulinemia often occurs in childhood and may be accompanied by hypothyroidism and hypogonadotropic hypogonadism.  Acanthosis nigricans and some degree of pulmonary dysfunction are common.  The majority of individuals (70%) develop restrictive or dilated cardiomyopathy, many in the first months of life, resulting in cardiac failure.  The liver may become cirrhotic and renal failure occurs late.  Intelligence is usually normal but many patients (25-30%) have early delays in their developmental milestones perhaps secondary to growth hormone deficiency which has been reported (98% are short in stature).  Lifespan is short and many die in childhood.  Few live beyond the age of 40 years.

Alstrom syndrome has some similarities to Bardet-Biedl syndrome (209900) but differs in the absence of mental deficiency and polydactyly.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the ALMS1 gene on chromosome 2 (2p13).  The ALMS1 protein product is found in many cells throughout the body and is located in centrosomes and the base of cilia.  Its function is unknown.

More than 320 mutations have been reported. However, many cases remain in which no mutation has been found suggesting additional genetic heterogeneity remains.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the basic disease.

References
Article Title: 

Alström Syndrome: Mutation Spectrum of ALMS1

Marshall JD, Muller J, Collin GB, Milan G, Kingsmore SF, Dinwiddie D, Farrow EG, Miller NA, Favaretto F, Maffei P, Dollfus H, Vettor R, Naggert JK. Alstrom Syndrome: Mutation Spectrum of ALMS1. Hum Mutat. 2015 Apr 2. doi: 10.1002/humu.22796. [Epub ahead of print].

PubMed ID: 
25846608

Alström syndrome

Marshall JD, Beck S, Maffei P, Naggert JK. Alstrom syndrome. Eur J Hum Genet. 2007 Dec;15(12):1193-202.

PubMed ID: 
17940554

Retinitis Pigmentosa, Deafness, Mental Retardation and Hypogonadism

Clinical Characteristics
Ocular Features: 

Only two families with this presumed disorder have been reported.  The retinal picture resembles retinitis pigmentosa with ‘bone spicule’ pigment clumps, vascular attenuation, and pale optic nerve heads.  Cataracts and nystagmus have been observed.  Vision is usually limited to light perception by the middle of the first decade of life.

Systemic Features: 

Small testes and gynecomastia are found in males while females have oligo- or amenorrhea.  The hands and feet appear broad and the face has a coarse appearance with a depressed nasal bridge and a broad nose.  Insulin-resistant diabetes and hyperinsulinemia are present.  Acanthosis nigricans, keloids, obesity, and hearing loss are also features.  All patients have significant developmental delays and evident mental retardation.

Genetics

No locus has been identified although autosomal recessive inheritance seems likely: the parents in one family were first cousins and there was no parent to child transmission.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no effective treatment although cataract surgery might be considered if lens opacities are visually significant.

References
Article Title: 

MELAS Syndrome

Clinical Characteristics
Ocular Features: 

This progressive mitochondrial disorder primarily affects muscles and the CNS, including the visual system.  The pattern of ocular deficits is not consistent and those that are present are not specific, requiring the clinician to take the entire neurological picture into consideration.  Hemianopsia, cortical blindness and ophthalmoplegia may be present.  The ERG can show reduced b-wave amplitudes and VEPs may be absent.  The optic nerve head has been described as normal without the atrophy often seen with other mitochondrial disorders.  A pigmentary retinopathy may be present.

Systemic Features: 

The clinical picture is highly variable.  Most commonly patients have myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.  The onset of symptoms is usually in the first two decades of life, most commonly consisting of headaches of sudden onset accompanied by vomiting and seizures.  The headaches may simulate migraines.  Weakness, lethargy, and apathy may be present early.  However, infants and young children may present with failure to thrive, developmental delay, and learning disabilities.  Neurosensory deafness is often seen and peripheral neuropathy is usually evident.  MRIs may show cerebellar hypoplasia and infarctions in the cerebral hemispheres.  Some patients have calcifications in the basal ganglia.  Patients may develop lactic acidosis.  Muscle biopsies often show ragged, red fibers.  The heart is commonly involved with both structural and rhythm defects.  Depending upon the degree and location of brain damage, patients may have hemiparesis, lethargy, ataxia, myoclonic jerks, cognitive decline, and dementia.  Morbidity and mortality are high.

Genetics

MELAS syndrome is a group of disorders caused by mutations in mitochondrial genes (at least 9 have been identified) that alter transfer RNA molecules resulting in disruption of intramitochondrial synthesis of proteins involved in oxidative phosphorylation pathways.  It is both clinically and genetically heterogeneous.  One can expect that any familial occurrence would result from maternal transmission but the occurrence of heteroplasmy results in considerable variability in the severity of clinical disease.

Treatment
Treatment Options: 

There is no effective treatment that prevents development of disease or that slows its progress.

References
Article Title: 
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