diabetes mellitus

Friedreich Ataxia 1

Clinical Characteristics
Ocular Features: 

Nystagmus and optic atrophy are important ocular signs.  The visual pathway, both anterior and posterior, is consistently involved and field defects are common even though many patients are asymptomatic.  OCT usually shows a reduced nerve fiber layer secondary to loss of axons.  About half of patients have abnormal visual evoked potentials.  A few patients experience a sudden loss of central vision during the second decade of life.

Systemic Features: 

Friedreich ataxia is a progressive neurodegenerative disorder with onset before puberty.  The spinocerebellar tracts, dorsal columns, pyramidal tracts, cerebellum, medulla, and optic radiation, may all be involved.  The outstanding symptom is ataxia with impairment of gait and weakness in the limbs.  Muscle weakness, extensor plantar responses, and absent lower limb reflexes are usually present.  Dysarthria is usually notable.  Sensory signs include impairment of position and vibratory senses.  'Twitching' in limbs and digits is often noted and 'restless leg syndrome' is common.

Secondary changes include pes cavus, scoliosis, and hammer toe.  Cardiac disease is frequently present and heart failure is the most common cause of death.  Most patients have hypertrophic cardiomyopathy with characteristic EKG changes and some have subaortic stenosis as part of the hypertrophied myocardium.  Diabetes mellitus is present in 20-25%.  Some hearing loss occurs in more than 10% of individuals.

Most patients require a wheelchair within 15 years of disease onset and the mean age of death is about 36 years.

Rare patients with a later onset of FRDA retain lower limb deep tendon reflexes.

Genetics

Homozygous mutations in FXN (9p21.11) are responsible for Friedreich ataxia.  The most common DNA abnormality is a GAA trinucleotide repeat expansion in intron 1.  The number of repeats in patients is 70 to more than 1000 compared with 5-30 in normal individuals.  FXN encodes the mitochondrial protein frataxin.

About 2% of individuals have point mutations in FXN instead of trinucleotide repeats.

Some of the phenotypic variations may be explained by differences in the number of GAA repeats.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is largely directed at symptoms including speech and physical therapy and mobility assistive devices. Scoliosis may require surgical intervention.

References
Article Title: 

Visual system involvement in patients with Friedreich's ataxia

Fortuna F, Barboni P, Liguori R, Valentino ML, Savini G, Gellera C, Mariotti C, Rizzo G, Tonon C, Manners D, Lodi R, Sadun AA, Carelli V. Visual system involvement in patients with Friedreich's ataxia. Brain. 2009 Jan;132(Pt 1):116-23.

PubMed ID: 
18931386

Friedreich ataxia: an overview

Delatycki MB, Williamson R, Forrest SM. Friedreich ataxia: an overview. J Med Genet. 2000 Jan;37(1):1-8. Review.

PubMed ID: 
10633128

Wolfram Syndrome 2

Clinical Characteristics
Ocular Features: 

As in Wolfram syndrome 1, only insulin dependent diabetes mellitus and optic atrophy are essential to the diagnosis. The optic atrophy is progressive over a period of years and can be the presenting sign.  Its onset, however, is highly variable and may begin in infancy but almost always before the third decade of life.  The majority (77%) of patients are legally blind within a decade of onset.  The visual field may show paracentral scotomas and peripheral constriction.  Both VEPs and ERGs can be abnormal.  Diabetic retinopathy is uncommon and usually mild.

Systemic Features: 

The clinical features of this disorder are many and highly variable.  Sensorineural hearing loss, anemia, seizures, ataxia, and autonomic neuropathy are usually present. Respiratory failure secondary to brain stem atrophy may have fatal consequences by the age of 30 years.  A variety of mental disturbances including mental retardation, dementia, depression, and behavioral disorders have been reported.  The diabetes mellitus is insulin dependent with childhood onset.  Hydroureter is often present.

Diabetes insipidus may be present in patients with Wolfram syndrome 1 (222300) but has not been reported in patients reported with Wolfram syndrome 2.   Upper GI ulceration and bleeding were present in several individuals.

Genetics

This is an autosomal recessive disorder similar to Wolfram syndrome 1 (WFS1; 222300) but caused by mutations in the CISD2 gene (4q22-q24).  The gene codes for a small protein (ERIS) localized to the endoplasmic reticulum. It seems to occur less commonly than WFS1.

Some patients have mutations in mitochondrial DNA as the basis for their disease (598500).  Combined with evidence that point mutations at the 4p16.1 locus predisposes deletions in mtDNA, this suggests that at least some patients with Wolfram syndrome have a recessive disease caused by mutations in both nuclear and mitochondrial genes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is supportive for specific organ disease.  Low vision aids may be helpful in selected individuals.

References
Article Title: 

Wolfram Syndrome 1

Clinical Characteristics
Ocular Features: 

Optic atrophy in association with diabetes mellitus is considered necessary to the diagnosis of Wolfram syndrome.  The optic atrophy is progressive over a period of years and can be the presenting symptom.  Its onset, however, is highly variable and may begin in infancy but almost always before the third decade of life.  The majority (77%) of patients are legally blind within a decade of onset.  The visual field may show paracentral scotomas and peripheral constriction.  Both VEPs and ERGs can be abnormal.  Diabetic retinopathy is uncommon and usually mild.

Two sibs with confirmed WFS1 have been reported with microspherophakia, congenital cataracts, and glaucoma in addition to optic atrophy .

Systemic Features: 

The clinical features of this disorder are many and highly variable.  Sensorineural hearing loss, diabetes insipidus, anemia, seizures, vasopressin deficiency, ataxia, and autonomic neuropathy are usually present. Respiratory failure secondary to brain stem atrophy may have fatal consequences by the age of 30 years.  A variety of mental disturbances including mental retardation, dementia, depression, and behavioral disorders have been reported.  The diabetes mellitus is insulin dependent with childhood onset.  Dilated ureters and neurogenic bladder are frequently seen, especially in older patients..

Genetics

Wolfram syndrome 1 is an autosomal recessive disorder that can be caused by mutations in the WFS1 gene (4p16.1) encoding wolframin, a small protein important to maintenance of the endoplasmic reticulum.  However, a minority of individuals also have deletion mutations in mitochondrial DNA (598500).  Some evidence suggests that point mutations at 4p16.1 predispose deletions in mtDNA, and, if so, this recessive disorder may owe its appearance to combined mutations in both nuclear and mitochondrial DNA.  In addition, rare families with the Wolfram syndrome phenotype and mutations in the WFS1 gene show transmission patterns consistent with autosomal dominant inheritance.

Wolfram syndrome 2 (WFS2) (604928) results from mutations in CISD2 at 4q22-q24.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for Wolfram syndrome but the administration of thiamin can correct the anemia.  Low vision aids may be helpful in early stages of disease.

References
Article Title: 

Lymphedema-Distichiasis Syndrome

Clinical Characteristics
Ocular Features: 

This form of lymphedema is associated with distichiasis, often with trichiasis and significant corneal damage in about 75% of patients.  Onset of symptoms may occur at any age but usually during childhood or adolescence.  Photophobia, epiphora, corneal erosions, ptosis, and partial ectropion of the lids may also be seen.  The secondary symptoms of trichiasis are not always present and slit lamp examination of the lashes may be necessary to see the duplicated row of lashes.  The lashes often grow out of the Meibomian orifices.

Systemic Features: 

Cardiac defects, cleft palate, and spinal extradural cysts occur in some families.  Type II diabetes and interstitial nephritis have been reported.  The lymph channels in the lower extremities may be normal or increased in number, especially below the knee where pitting edema is most often first seen, even as early as the first decade of life.  Lymphedema occurs earlier in males and secondary cellulitis is a greater risk. It is usually confined to the lower extremities and is often asymmetrical.  Not all patients have the complete syndrome, while lymphedema and distichiasis can be inherited as individual disorders without being associated.  Males are more likely to have the complete syndrome.

Several families with this syndrome secondary to mutations in the FOXC2 have been reported to have renal anomalies ranging from kidney agenesis to malrotation. 

Genetics

This disorder is inherited in an autosomal dominant pattern and several families have been found to have mutations in the FOXC2 gene on chromosome 16 (16q24.3).  A Chinese family with an affected father and two affected offspring (one male and one female) has been reported with distichiasis but no lymphedema.  A premature stop codon was found in the FOXC2 transcription gene (16q24.1) in these family members suggesting that they may have had the lymphedema-distichiasis syndrome instead.

Blatt distichiasis is a unique disorder without the lymphedema (126300). 

Double rows of eyelashes are also part of the blepharocheilodontic syndrome (119580).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Electrolysis of individual misdirected lashes can be applied.  Prompt treatment of lid cellulitis is important. Surgical repair of scarred lid tissue can restore cosmesis lid function and improve cosmesis.

References
Article Title: 

Renal anomalies and lymphedema distichiasis syndrome

Jones GE, Richmond AK, Navti O, Mousa HA, Abbs S, Thompson E, Mansour S, Vasudevan PC. Renal anomalies and lymphedema distichiasis syndrome. A rare association? Am J Med Genet A. 2017 May;173(8):2251-2256.

PubMed ID: 
28544699

Hereditary lymphedema and distichiasis

Kolin T, Johns KJ, Wadlington WB, Butler MG, Sunalp MA, Wright KW. Hereditary lymphedema and distichiasis. Arch Ophthalmol. 1991 Jul;109(7):980-1.

PubMed ID: 
2064580
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