hypoalbuminemia

Mitochondrial DNA Depletion Syndrome 3

Clinical Characteristics
Ocular Features: 

Nystagmus, disconjugate eye movements, and "optic dysplasia" have been noted.

Systemic Features: 

Infants feed poorly which is frequently associated with vomiting, failure to thrive, and growth delay.  They are hypothermic, hypoglycemic, and often jaundiced with signs of liver failure noted between birth and 6 months of age and death by approximately 1 year of age.  Hepatosplenomegaly is present early with abnormal liver enzymes, cholestasis, steatosis, and hepatocellular loss followed by cirrhosis with portal hypertension.  Metabolic acidosis, hyperbilirubinemia, hypoalbuminemia, and hypoglycemia are often present.  Mitochondrial DNA depletion in the liver approaches 84-90%.

All patients have encephalopathic signs with evidence of cerebral atrophy, microcephaly, hypotonia.  Hyperreflexia may be present and some infants have seizures.  Muscle tissue, however, has normal histology and respiratory chain activity.

Genetics

This disorder results from homozygous or compound heterozygous mutations in the DGUOK gene (2p13).

The same gene is mutated in PEOB4 (617070).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no effective treatment.  Liver transplantation in one infant was unsuccessful.  

References
Article Title: 

Ataxia with Oculomotor Apraxia 1

Clinical Characteristics
Ocular Features: 

Patients with this disorder have difficulty initiating voluntary ocular movements upon command or when following targets (oculomotor apraxia).  Gaze changes are often initiated first by head thrusting, followed by saccadic eye movements.  One may test for this by holding the head whereupon the patient is unable to move the eyes.  Ocular apraxia is often evident a few years after symptoms of ataxia are noted and may progress to external ophthalmoplegia.  Most patients have exaggerated blinking.

Systemic Features: 

The ataxia is cerebellar in origin with onset usually in the first decade of life (mean age of onset 4.3 years). It is associated with peripheral axonal neuropathy and hypoalbuminemia. Gait imbalance is usually the first symptom followed by upper limb dysmetria.  Other variable signs include dysarthria, choreiform or athetoid movements, facial grimacing, tongue and limb fasciculations, areflexia, and distal sensory deficits.   All symptoms are progressive and ambulation is lost within a decade of onset.  Cerebellar atrophy may be seen on MRI and the EMG shows evidence of axonal neuropathy.  Mental function is normal in most patients but some have cognitive impairments.

Genetics

Mutations in the APTX gene (9p21.1) encoding aprataxin are responsible for this autosomal recessive condition. 

There is evidence of clinical and genetic heterogeneity.  At least two loci are involved, with the mutation at 9p13 causing an earlier onset of disease (first decade), and hypoalbuminemia, while the second one, ataxia with oculomotor apraxia 2  [606002]) at 9q34 causes a disorder of later onset (2nd or third decade) in which oculomotor apraxia is an inconsistent finding.  Oculomotor apraxia is more consistently found in the disorder described here.  Cogan-type oculomotor apraxia (257550) lacks other neurologic signs.

See also Ataxia with Oculomotor Apraxia 3 (615217), and Ataxia with Oculomotor Apraxia 4 (616267).

Oculomotor apraxia may be the presenting sign in Gaucher disease (230800, 230900, 231000). 

The ocular phenotype is similar to that seen in ataxia-telangiectasia (208900).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available although physical therapy can be helpful.

References
Article Title: 

Aprataxin gene mutations in Tunisian families

Amouri R, Moreira MC, Zouari M, El Euch G, Barhoumi C, Kefi M, Belal S, Koenig M, Hentati F. Aprataxin gene mutations in Tunisian families. Neurology. 2004 Sep 14;63(5):928-9.

PubMed ID: 
15365154
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