respiratory failure

Nemaline Myopathy 10

Clinical Characteristics
Ocular Features: 

Ophthalmoplegia has been reported in 29% of patients.

Systemic Features: 

In this form of nemaline myopathy, polyhydramnios, weak or absent fetal movements, and joint contractures may be noted during the antenatal period.  Hypotonia and generalized weakness, respiratory difficulties, feeding difficulties and evidence of bulbar weakness may be noted at birth.  Many patients die of respiratory failure in the neonatal period but some may survive into the second decade. 

Cardiac function is normal.

Genetics

This autosomal recessive disorder results from homozygous or compound heterozygous mutations in the LMOD3 gene (3p14.1).  This gene is expressed in both skeletal and cardiac muscle and its product is essential for the organization of sarcomeric thin filaments in skeletal muscle.

Mutations in at least 10 genes cause nemaline myopathy.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No general treatment is available for this condition but supportive care such as respiratory assistance and feeding supplementation may be helpful.  Physical therapy and special education may be helpful.

References
Article Title: 

Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy

Yuen M, Sandaradura SA, Dowling JJ, Kostyukova AS, Moroz N, Quinlan KG, Lehtokari VL, Ravenscroft G, Todd EJ, Ceyhan-Birsoy O, Gokhin DS, Maluenda J, Lek M, Nolent F, Pappas CT, Novak SM, D'Amico A, Malfatti E, Thomas BP, Gabriel SB, Gupta N, Daly MJ, Ilkovski B, Houweling PJ, Davidson AE, Swanson LC, Brownstein CA, Gupta VA, Medne L, Shannon P, Martin N, Bick DP, Flisberg A, Holmberg E, Van den Bergh P, Lapunzina P, Waddell LB, Sloboda DD, Bertini E, Chitayat D, Telfer WR, Laquerriere A, Gregorio CC, Ottenheijm CA, Bonnemann CG, Pelin K, Beggs AH, Hayashi YK, Romero NB, Laing NG, Nishino I, Wallgren-Pettersson C, Melki J, Fowler VM, MacArthur DG, North KN, Clarke NF. Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy. J Clin Invest. 2014 Nov;124(11):4693-708. Erratum in: J Clin Invest. 2015 Jan;125(1):456-7.

PubMed ID: 
25250574

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: 
Subscribe to RSS - respiratory failure